Novel dosage forms of rofecoxib and related methods

ABSTRACT

The subject matter disclosed herein relates to novel doses and dosage forms of rofecoxib having a therapeutic benefit.

This application is a continuation of International Patent ApplicationNo. PCT/US2020/060152, filed Nov. 12, 2020, which claims the benefit ofand priority under 35 U.S.C. § 119(e) to U.S. application Ser. No.16/867,514, filed May 5, 2020, which claims the benefit of and priorityunder 35 U.S.C. § 119(e) to each of U.S. Provisional Application No.63/018,136 filed Apr. 30, 2020 and U.S. Provisional Application No.62/934,898 filed Nov. 13, 2019, the contents of each of which isincorporated herein by reference in their entireties.

All patents, patent applications and publications cited herein arehereby incorporated by reference in their entirety. The disclosures ofthese publications in their entireties are hereby incorporated byreference into this application.

This patent disclosure contains material that is subject to copyrightprotection. The copyright owner has no objection to the facsimilereproduction by anyone of the patent document or the patent disclosureas it appears in the U.S. Patent and Trademark Office patent file orrecords, but otherwise reserves any and all copyright rights.

BACKGROUND OF THE INVENTION

Rofecoxib is a selective COX-2 inhibitor, nonsteroidal anti-inflammatorydrug (NSAID), that was marketed under the brand name “VIOXX” until itwas withdrawn from the market in at least 2004 over safety concerns.Before being withdrawn from the market, “VIOXX” was approved in theUnited States for the following indications: signs and symptoms ofosteoarthritis (OA); signs and symptoms of rheumatoid arthritis (RA) inadults; signs and symptoms of pauciarticular or polyarticular courseJuvenile Rheumatoid Arthritis; management of acute pain in adults;treatment of primary dysmenorrhea; and treatment of migraine attackswith or without aura in adults.

“VIOXX” was formulated in 12.5 mg, 25 mg, and 50 mg tablet dosage formsfor oral administration. Rapid and complete absorption is important tothe therapeutic efficacy of a drug. The bioavailability of solid oraldosages of drugs can be limited by poor dissolution into aqueous bodilyfluids. The bioavailability of “VIOXX” was previously reported to be93%, as provided in the FDA-approved label for the product. Asrofecoxib, the active ingredient in “VIOXX”, is a poorly water-solublemolecule, the reported 93% bioavailability was an exceptionally highvalue for an oral solid dosage form.

SUMMARY OF THE INVENTION

In certain aspects, the subject matter disclosed herein provides a soliddosage formulation comprising 17.5 mg of rofecoxib and apharmaceutically acceptable carrier.

In some embodiments, the rofecoxib formulation reaches a median time toCmax plasma concentration in 4 hours or less following a singleadministration of the formulation to human subjects less than 65 yearsof age. In some embodiments, the rofecoxib formulation reaches a mediantime to Cmax plasma concentration in 3.5 hours or less following asingle administration of the formulation to human subjects less than 65years of age. In some embodiments, the rofecoxib formulation reaches amedian time to Cmax plasma concentration in 3 hours or less following asingle administration of the formulation to human subjects less than 65years of age. In some embodiments, the rofecoxib formulation reaches amedian time to Cmax plasma concentration in 2.5 hours or less followinga single administration of the formulation to human subjects less than65 years of age.

In certain aspects, the subject matter disclosed herein provides a soliddosage formulation comprising 17.5 mg of rofecoxib and apharmaceutically acceptable carrier, wherein the formulation achieves amean Cmax plasma concentration of more than 100 ng/ml following a singleadministration of the formulation to human subjects less than 65 yearsof age.

In some embodiments, the rofecoxib formulation achieves a mean Cmaxplasma concentration of more than 150 ng/ml, 167 ng/ml, or 190 ng/ml. Insome embodiments, the rofecoxib formulation achieves a mean Cmax plasmaconcentration of more than 200 ng/ml. In some embodiments, the rofecoxibformulation achieves a mean Cmax plasma concentration of more than 220ng/ml. In some embodiments, the rofecoxib formulation achieves a meanCmax plasma concentration of more than 250 ng/ml.

In certain aspects, the subject matter disclosed herein provides a soliddosage formulation comprising 17.5 mg of rofecoxib and apharmaceutically acceptable carrier, wherein the formulation achieves amean AUC_(0-∞) of more than 1750 h*ng/ml following a singleadministration of the formulation to human subjects less than 65 yearsof age.

In some embodiments, the rofecoxib formulation achieves a mean AUC_(0-∞)of more than 2000 h*ng/ml following a single administration of theformulation to human subjects less than 65 years of age. In someembodiments, the rofecoxib formulation achieves a mean AUC_(0-∞) of morethan 2500 h*ng/ml following a single administration of the formulationto human subjects less than 65 years of age. In some embodiments, therofecoxib formulation achieves a mean AUC_(0-∞) of more than 3000h*ng/ml following a single administration of the formulation to humansubjects less than 65 years of age. In some embodiments, the rofecoxibformulation achieves a mean AUC_(0-∞) of more than 3100 h*ng/mlfollowing a single administration of the formulation to human subjectsless than 65 years of age. In some embodiments, the rofecoxibformulation achieves a mean AUC_(0-∞) of more than 3500 h*ng/mlfollowing a single administration of the formulation to human subjectsless than 65 years of age.

In some embodiments, the rofecoxib formulation further comprises agranular component and an extragranular component, wherein the granularcomponent comprises an intragranular component comprising the rofecoxiband one or more disintegrants, and wherein the extragranular componentcomprises one or more disintegrants. In some embodiments, the rofecoxibin the formulation has a d90 particle size from about 10-12 μm, a d50particle size from about 3-4 μm, and a d10 particle size from about0.5-1.0 μm.

In certain aspects, the subject matter disclosed herein provides a soliddosage formulation comprising 20 mg of rofecoxib and a pharmaceuticallyacceptable carrier.

In some embodiments, the formulation reaches a median time to Cmaxplasma concentration in 4 hours or less following a singleadministration of the formulation to human subjects less than 65 yearsof age. In some embodiments, the formulation reaches a median time toCmax plasma concentration in 3 hours or less following administration.In some embodiments, the formulation reaches a mean Cmax plasmaconcentration in less than 3 hours following administration. In someembodiments, the formulation reaches a median time to Cmax plasmaconcentration in 2.5 hours or less following administration.

In certain aspects, the subject matter disclosed herein provides a soliddosage formulation comprising 20 mg of rofecoxib and a pharmaceuticallyacceptable carrier, wherein the formulation achieves a mean Cmax plasmaconcentration of more than 150 ng/ml following a single administrationof the formulation to human subjects less than 65 years of age.

In some embodiments, the rofecoxib formulation achieves a mean Cmaxplasma concentration of more than 191 ng/ml, 200 ng/ml, 215 ng/ml, or225 ng/ml following a single administration of the formulation to humansubjects less than 65 years of age. In some embodiments, the rofecoxibformulation achieves a mean Cmax plasma concentration of more than 250ng/ml following a single administration of the formulation to humansubjects less than 65 years of age. In some embodiments, the rofecoxibformulation achieves a mean Cmax plasma concentration of more than 258ng/ml following a single administration of the formulation to humansubjects less than 65 years of age. In some embodiments, the rofecoxibformulation achieves a mean Cmax plasma concentration of more than 300ng/ml following a single administration of the formulation to humansubjects less than 65 years of age.

In certain aspects, the subject matter disclosed herein provides a soliddosage formulation comprising 20 mg of rofecoxib and a pharmaceuticallyacceptable carrier, wherein the formulation achieves a mean AUC_(0-∞) ofmore than 2000 h*ng/ml following a single administration of theformulation to human subjects less than 65 years of age.

In some embodiments, the formulation achieves a mean AUC_(0-∞) of morethan 2500 h*ng/ml following a single administration of the formulationto human subjects less than 65 years of age. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 3000 h*ng/mlfollowing a single administration of the formulation to human subjectsless than 65 years of age. In some embodiments, the formulation achievesa mean AUC_(0-∞) of more than 3400 h*ng/ml following a singleadministration of the formulation to human subjects less than 65 yearsof age. In some embodiments, the formulation achieves a mean AUC_(0-∞)of more than 3500 h*ng/ml following a single administration of theformulation to human subjects less than 65 years of age. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 3550h*ng/ml following a single administration of the formulation to humansubjects less than 65 years of age.

In some embodiments, the formulation further comprises a granularcomponent and an extragranular component, wherein the granular componentcomprises an intragranular component comprising the rofecoxib and one ormore disintegrants, and wherein the extragranular component comprisesone or more disintegrants. In some embodiments, the rofecoxib in theformulation has a d90 particle size from about 10-12 μm, a d50 particlesize from about 3-4 μm, and a d10 particle size from about 0.5-1.0 μm.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 25 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof, wherein the formulationachieves a mean Cmax plasma concentration in less than 3 hours followinga single administration of the formulation to human subjects less than65 years of age.

In some embodiments, the rofecoxib formulation achieves a median time toCmax plasma concentration in 2.5 hours or less following administrationof the formulation to human subjects less than 65 years of age.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 25 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof, wherein the formulationachieves a mean Cmax plasma concentration of more than 250 ng/mlfollowing a single administration of the formulation to human subjectsless than 65 years of age.

In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 300 ng/ml following administration of theformulation to human subjects less than 65 years of age. In someembodiments, the formulation achieves a mean Cmax plasma concentrationof more than 320 ng/ml following administration of the formulation tohuman subjects less than 65 years of age. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 350ng/ml following administration of the formulation to human subjects lessthan 65 years of age.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 25 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof, wherein the formulationachieves a mean AUC_(0-∞) of more than 4250 h*ng/ml following a singleadministration of the formulation to human subjects less than 65 yearsof age.

In some embodiments, the formulation achieves a mean AUC_(0-∞) of morethan 4500 h*ng/ml following administration of the formulation to humansubjects less than 65 years of age. In some embodiments, the formulationachieves a mean AUC_(0-∞) of more than 4700 h*ng/ml followingadministration of the formulation to human subjects less than 65 yearsof age. In some embodiments, the formulation achieves a mean AUC_(0-∞)of more than 5000 h*ng/ml following administration of the formulation tohuman subjects less than 65 years of age. In some embodiments, theformulation further comprises a granular component and an extragranularcomponent, wherein the granular component comprises an intragranularcomponent comprising the rofecoxib and one or more disintegrants, andwherein the extragranular component comprises one or more disintegrants.

In some embodiments, the rofecoxib in the formulation has a d90 particlesize from about 10-12 μm, a d50 particle size from about 3-4 μm, and ad10 particle size from about 0.5-1.0 μm.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 25 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof, wherein a singleadministration of the formulation to human subjects achieves a mean Cmaxplasma concentration of more than 240 ng/ml in less than 3 hoursfollowing administration with a mean AUC_(0-∞) of more than 4250h*ng/ml.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 17.5 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof.

In some embodiments, the rofecoxib formulation achieves a median time toCmax plasma concentration in 4 hours or less following a singleadministration of the formulation to human subjects less than 65 yearsof age. In some embodiments, the rofecoxib formulation achieves a mediantime to Cmax plasma concentration in 3.5 hours or less followingadministration. In some embodiments, the rofecoxib formulation achievesa median time to Cmax plasma concentration in 3 hours or less followingadministration. In some embodiments, the rofecoxib formulation achievesa median time to Cmax plasma concentration in 2.5 hours or lessfollowing administration.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 17.5 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof, wherein a singleadministration of the formulation to human subjects less than 65 yearsof age achieves a mean Cmax plasma concentration of more than 100 ng/ml.

In some embodiments, the rofecoxib formulation achieves a mean Cmaxplasma concentration of more than 150 ng/ml, 167 ng/ml, or 190 ng/ml. Insome embodiments, the rofecoxib formulation achieves a mean Cmax plasmaconcentration of more than 200 ng/ml. In some embodiments, the rofecoxibformulation achieves a mean Cmax plasma concentration of more than 220ng/ml. In some embodiments, the rofecoxib formulation achieves a meanCmax plasma concentration of more than 250 ng/ml.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 17.5 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof, wherein a singleadministration of the formulation to human subjects less than 65 yearsof age achieves a mean AUC_(0-∞) of more than 1750 h*ng/ml.

In some embodiments, the rofecoxib formulation achieves a mean AUC_(0-∞)of more than 2000 h*ng/ml. In some embodiments, the rofecoxibformulation achieves a mean AUC_(0-∞) of more than 2500 h*ng/ml. In someembodiments, the rofecoxib formulation achieves a mean AUC_(0-∞) of morethan 3000 h*ng/ml. In some embodiments, the rofecoxib formulationachieves a mean AUC_(0-∞) of more than 3100 h*ng/ml. In someembodiments, the rofecoxib formulation achieves a mean AUC_(0-∞) of morethan 3500 h*ng/ml.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 17.5 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof, wherein a singleadministration of the formulation to human subjects less than 65 yearsof age achieves a mean Cmax plasma concentration within 80% to 125% of224 ng/ml.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 17.5 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof, wherein the formulationreaches a Cmax plasma concentration of least 170 ng/ml in the subject.

In some embodiments, the formulation reaches a Cmax plasma concentrationlevel of at least 175 ng/ml. In some embodiments, the formulationreaches a Cmax plasma concentration level of at least 180 ng/ml. In someembodiments, the formulation reaches a Cmax plasma concentration levelof at least 185 ng/ml. In some embodiments, the formulation reaches aCmax plasma concentration level of at least 190 ng/ml.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 17.5 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof, wherein the formulationreaches an AUC_(0-∞) of more than 2600 h*ng/ml in the subject.

In some embodiments, the rofecoxib formulation reaches an AUC_(0-∞) ofmore than 2750 h*ng/ml. In some embodiments, the rofecoxib formulationreaches an AUC_(0-∞) of more than 2900 h*ng/ml. In some embodiments, therofecoxib formulation reaches an AUC_(0-∞) of more than 3050 h*ng/ml. Insome embodiments, the rofecoxib formulation reaches an AUC_(0-∞) of morethan 3200 h*ng/ml. In some embodiments, the rofecoxib formulationreaches an AUC_(0-∞) of more than 3350 h*ng/ml.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 20 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof.

In some embodiments, the rofecoxib formulation achieves a median time toCmax plasma concentration in 4 hours or less following a singleadministration of the formulation to human subjects. In someembodiments, the rofecoxib formulation achieves a median time to Cmaxplasma concentration in 3.5 hours or less following administration. Insome embodiments, the rofecoxib formulation achieves a median time toCmax plasma concentration in 3 hours or less following administration.In some embodiments, the rofecoxib formulation achieves a median time toCmax plasma concentration in 2.5 hours or less following administration.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 20 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof, wherein a singleadministration of the formulation to human subjects less than 65 yearsof age achieves a mean Cmax plasma concentration of more than 150 ng/ml.

In some embodiments, the rofecoxib formulation achieves a mean Cmaxplasma concentration of more than 191 ng/ml, 200 ng/ml, 215 ng/ml, or225 ng/ml. In some embodiments, the rofecoxib formulation achieves amean Cmax plasma concentration of more than 250 ng/ml. In someembodiments, the rofecoxib formulation achieves a mean Cmax plasmaconcentration of more than 258 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 300ng/ml.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 20 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof, wherein a singleadministration of the formulation to human subjects less than 65 yearsof age achieves a mean AUC_(0-∞) of more than 2000 h*ng/ml.

In some embodiments, the rofecoxib formulation achieves a mean AUC_(0-∞)of more than 2500 h*ng/ml. In some embodiments, the rofecoxibformulation achieves a mean AUC_(0-∞) of more than 3000 h*ng/ml. In someembodiments, the rofecoxib formulation achieves a mean AUC_(0-∞) of morethan 3400 h*ng/ml. In some embodiments, the rofecoxib formulationachieves a mean AUC_(0-∞) of more than 3500 h*ng/ml.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 20 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof, wherein a singleadministration of the formulation to human subjects less than 65 yearsof age achieves a mean Cmax plasma concentration within 80% to 125% of259 ng/ml.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 20 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof, wherein the formulationreaches a Cmax plasma concentration of least 170 ng/ml in the subject.

In some embodiments, the rofecoxib formulation reaches a Cmax plasmaconcentration level of at least 190 ng/ml. In some embodiments, therofecoxib formulation reaches a Cmax plasma concentration level of atleast 205 ng/ml. In some embodiments, the rofecoxib formulation reachesa Cmax plasma concentration level of at least 220 ng/ml. In someembodiments, the rofecoxib formulation reaches a Cmax plasmaconcentration level of at least 235 ng/ml. In some embodiments, therofecoxib formulation reaches a Cmax plasma concentration level of atleast 250 ng/ml.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 20 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof, wherein the formulationreaches an AUC_(0-∞) of more than 3000 h*ng/ml in the subject.

In some embodiments, the rofecoxib formulation reaches an AUC_(0-∞) ofmore than 3200 h*ng/ml. In some embodiments, the rofecoxib formulationreaches an AUC_(0-∞) of more than 3300 h*ng/ml. In some embodiments, therofecoxib formulation reaches an AUC_(0-∞) of more than 3500 h*ng/ml. Insome embodiments, the rofecoxib formulation reaches an AUC_(0-∞) of morethan 3500 h*ng/ml. In some embodiments, the rofecoxib formulationreaches an AUC_(0-∞) of more than 3525 h*ng/ml. In some embodiments, therofecoxib formulation reaches an AUC_(0-∞) of 3550 h*ng/ml or more. Insome embodiments, the rofecoxib formulation achieves a mean Cmax plasmaconcentration within 80% to 125% of 259 ng/ml and a mean AUC_(0-∞)within 80% to 125% of 3550 h*ng/ml. In some embodiments, the rofecoxibformulation achieves a mean plasma AUC_(0-∞) of about 2840-4438 h*ng/mland a mean plasma Cmax of about 207-324 ng/ml following oraladministration of a single dose of the formulation to a population ofhealthy adults less than 65 years of age in a fasted state. In someembodiments, the population of healthy adults are less than 60 years ofage.

In certain aspects, the subject matter disclosed herein provides apharmaceutically acceptable formulation comprising a granular componentand an extragranular component, wherein the granular component comprisesan intragranular component comprising rofecoxib or a pharmaceuticallyacceptable salt thereof and one or more disintegrants, and wherein theextragranular component comprises one or more disintegrants.

In some embodiments, the one or more disintegrants in the granularcomponent is selected from starches, clays, celluloses, algins, gums,cross-linked polymers, and combinations thereof. In some embodiments,the one or more disintegrants in the granular component is selected fromcroscarmellose, crospovidone, sodium starch glycolate, and combinationsthereof. In some embodiments, one or more disintegrants in the granularcomponent is croscarmellose sodium. In some embodiments, the one or moredisintegrants in the granular component is about 1% (w/w) to about 8%(w/w) of the formulation. In some embodiments, the one or moredisintegrants in the granular component is about 1% (w/w) to about 6%(w/w) of the formulation. In some embodiments, the one or moredisintegrants in the granular component is about 1% (w/w) to about 4%(w/w) of the formulation. In some embodiments, the one or moredisintegrants in the extragranular component is selected from starches,clays, celluloses, algins, gums, cross-linked polymers, and combinationsthereof. In some embodiments, the one or more disintegrants in theextragranular component is selected from croscarmellose, crospovidone,sodium starch glycolate, and combinations thereof. In some embodiments,the one or more disintegrants in the extragranular component iscroscarmellose sodium.

In some embodiments, the disintegrant in the extragranular component isabout 1% (w/w) to about 8% (w/w) of the formulation. In someembodiments, the disintegrant in the extragranular component is about 1%(w/w) to about 6% (w/w) of the formulation. In some embodiments, thedisintegrant in the extragranular component is about 1% (w/w) to about4% (w/w) of the formulation. In some embodiments, the disintegrant inthe granular component and the disintegrant in the extragranularcomponent are together about 2% (w/w) to about 12% (w/w) of theformulation. In some embodiments, the disintegrant in the granularcomponent and the disintegrant in the extragranular component aretogether about 2% (w/w) to about 10% (w/w) of the formulation. In someembodiments, the disintegrant in the granular component and thedisintegrant in the extragranular component are together about 2% (w/w)to about 8% (w/w) of the formulation. In some embodiments, the ratio ofgranular disintegrant to extragranular disintegrant is about 40% toabout 60% (w/w). In some embodiments, the ratio of granular disintegrantto extragranular disintegrant is about 45% to about 55% (w/w). In someembodiments, the ratio of granular disintegrant to extragranulardisintegrant is about 50% to about 50% (w/w). In some embodiments, theratio of granular disintegrant to extragranular disintegrant is about55% to about 45% (w/w). In some embodiments, the ratio of granulardisintegrant to extragranular disintegrant is about 60% to about 40%(w/w).

In some embodiments, the pharmaceutically acceptable formulation formfurther comprises one or more of a diluent, a binder, a coloring agent,and a lubricant. In some embodiments, at least a portion of the diluentis in the granular component. In some embodiments, the diluent isselected from dicalcium phosphate, calcium sulfate, lactose, cellulose,kaolin, mannitol, sodium chloride, dry starch, powdered sugar, sorbitol,sucrose, inositol, and combinations thereof. In some embodiments, thediluent is selected from lactose, cellulose, or a combination thereof.In some embodiments, the diluent is selected from lactose monohydrate,microcrystalline cellulose, or a combination thereof.

In some embodiments, the lactose monohydrate is about 35% (w/w) to about45% (w/w) of the formulation. In some embodiments, the lactosemonohydrate is about 37% (w/w) to about 42% (w/w) of the formulation. Insome embodiments, the lactose monohydrate is about 39% (w/w) to about40% (w/w) of the formulation. In some embodiments, the microcrystallinecellulose is about 35% (w/w) to about 45% (w/w) of the formulation. Insome embodiments, the microcrystalline cellulose is about 37% (w/w) toabout 42% (w/w) of the formulation. In some embodiments, themicrocrystalline cellulose is about 39% (w/w) to about 40% (w/w) of theformulation. In some embodiments, the diluent is about 75% (w/w) toabout 85% (w/w) of the formulation. In some embodiments, the diluent isabout 77% (w/w) to about 82% (w/w) of the formulation. In someembodiments, the diluent is about 78% (w/w) to about 80% (w/w) of theformulation.

In some embodiments, at least a portion of the binder is in the granularcomponent. In some embodiments, the binder is selected from starches,gelatins, sugars, gums, waxes, water, alcohols, celluloses, andcombinations thereof. In some embodiments, the binder is selected fromacacia gum, tragacanth, corn starch, methyl cellulose, panwar gum,ghatti gum, mucilage of isapol husks, carboxymethylcellulose,methylcellulose, polyvinylpyrrolidone, sucrose, glucose, dextrose,molasses, lactose, and combinations thereof. In some embodiments, thebinder is hydroxypropyl cellulose.

In some embodiments, the binder is about 1% (w/w) to about 5% (w/w) ofthe formulation. In some embodiments, the binder is about 2% (w/w) toabout 4% (w/w) of the formulation. In some embodiments, the binder isabout 2.5% (w/w) to about 3.5% (w/w) of the formulation.

In some embodiments, at least a portion of the coloring agent is in theextragranular component. In some embodiments, the coloring agent ispigment blend yellow. In some embodiments, the coloring agent is about0.30% (w/w) to about 0.60% (w/w) of the formulation.

In some embodiments, at least a portion of the lubricant is in theextragranular component. In some embodiments, the lubricant is selectedfrom talc, magnesium stearate, calcium stearate, stearic acid, metallicstearate, hydrogenated vegetable oils, and polyethylene glycol, cornstarch, boric acids, sodium chloride, sodium lauryl sulphate. In someembodiments, the lubricant is magnesium stearate. In some embodiments,the lubricant is about 0.10% (w/w) to about 1% (w/w) of the formulation.In some embodiments, the lubricant is about 0.50% (w/w) of theformulation.

In some embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is about 5% (w/w) to about 30% (w/w) of the formulation. In someembodiments, the rofecoxib or pharmaceutically acceptable salt thereofis about 10% (w/w) to about 20% (w/w) of the formulation. In someembodiments, the rofecoxib or pharmaceutically acceptable salt thereofis about 12% (w/w) to about 13% (w/w) of the formulation.

In some embodiments, the formulation comprises about 10 mg of therofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the formulation comprises about 12.5 mg of the rofecoxib orpharmaceutically acceptable salt thereof. In some embodiments, theformulation comprises about 17.5 mg of the rofecoxib or pharmaceuticallyacceptable salt thereof. In some embodiments, the formulation comprisesabout 20 mg of the rofecoxib or pharmaceutically acceptable saltthereof. In some embodiments, the formulation comprises about 25 mg ofthe rofecoxib or pharmaceutically acceptable salt thereof.

In some embodiments, the rofecoxib is substantially pure. In someembodiments, the rofecoxib is highly pure. In some embodiments, thehighly pure rofecoxib comprises less than about 0.1% total impurities.In some embodiments, the highly pure rofecoxib comprises less than about0.075% total impurities. In some embodiments, the highly pure rofecoxibcomprises less than about 0.050% total impurities. In some embodiments,the highly pure rofecoxib comprises less than about 0.025% totalimpurities. In some embodiments, the highly pure rofecoxib comprisesless than about 0.001% total impurities.

In some embodiments, the rofecoxib is substantially pure or highly pure.In some embodiments, the highly pure rofecoxib comprises less than about0.10%, 0.05%, 0.02%, or 0.01% of4-[4-(methylsulphonyl)phenyl]-3-phenyl-2,5-furandione. In someembodiments, the highly pure rofecoxib comprises less than about 0.10%,0.05%, 0.02%, or 0.01% of4-[4-(methylsulfonyl)phenyl]-3-phenyl-5-hydroxyfuran-2-one. In someembodiments, the highly pure rofecoxib comprises less than about 0.10%,0.05%, 0.02%, or 0.01% of4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some embodiments,the highly pure rofecoxib comprises less than about 0.10%, 0.05%, 0.02%,or 0.01% of 4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone.

In some embodiments, the formulation is suitable for oraladministration. In some embodiments, the formulation is a solid dosageform. In some embodiments, the solid dosage form is an oral tablet.

In some embodiments, the oral tablet provides a dissolution rate of atleast about 80% of the rofecoxib or pharmaceutically acceptable saltthereof by about 15 minutes. In some embodiments, the oral tabletprovides a dissolution rate of at least about 85% of the rofecoxib orpharmaceutically acceptable salt thereof by about 15 minutes. In someembodiments, the oral tablet provides a dissolution rate of at leastabout 90% of the rofecoxib or pharmaceutically acceptable salt thereofby about 15 minutes. In some embodiments, the oral tablet provides adissolution rate of at least about 95% of the rofecoxib orpharmaceutically acceptable salt thereof by about 15 minutes. In someembodiments, the oral tablet provides a dissolution rate of at leastabout 100% of the rofecoxib or pharmaceutically acceptable salt thereofby about 15 minutes.

In some embodiments, the dissolution rate is measured in about 1% SDS ata paddle speed of about 50 rpm and at a temperature of about 37.0°C.±0.5° C. In some embodiments, the dissolution rate is measured inabout 1% SDS at a paddle speed of about 75 rpm and at a temperature ofabout 37.0° C.±0.5° C. In some embodiments, the dissolution rate ismeasured in about 1.5% SDS at a paddle speed of about 50 rpm and at atemperature of about 37.0° C.±0.5° C. In some embodiments, thedissolution rate is measured in about 1.5% SDS at a paddle speed ofabout 75 rpm and at a temperature of about 37.0° C.±0.5° C. In someembodiments, the dissolution rate is measured in about 2% SDS at apaddle speed of about 50 rpm and at a temperature of about 37.0° C.±0.5°C. In some embodiments, the dissolution rate is measured in about 2% SDSat a paddle speed of about 75 rpm and at a temperature of about 37.0°C.±0.5° C. In some embodiments, the dissolution rate is measured using aUSP Type II apparatus. In some embodiments, the dissolution rate ismeasured with a USP Type II apparatus using 900 mL of 2% SDS, a paddlespeed of 50 rpm, and a temperature of 37.0° C.±0.5°.

In some embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 35% of thegranules are less than about 75 μm. In some embodiments, the rofecoxibor pharmaceutically acceptable salt thereof is formulated into granulesand at least about 55% of the granules are less than about 150 μm. Insome embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 75% of thegranules are less than about 250 μm. In some embodiments, the rofecoxibor pharmaceutically acceptable salt thereof is formulated into granulesand at least about 85% of the granules are less than about 425 μm. Insome embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 90% of thegranules are less than about 1000 μm.

In some embodiments, the formulation is a solid dosage formulationcomprising 12.5 mg, 17.5 mg, 20 mg, or 25 mg of rofecoxib, and whereinthe formulation reaches a median time to Cmax plasma concentration in 3hours or less following a single administration of the formulation tohuman subjects less than 65 years of age.

In some embodiments, the formulation reaches a mean Cmax plasmaconcentration in less than 3 hours following administration. In someembodiments, the formulation reaches a mean Cmax plasma concentration inless than 2.5 hours following administration. In some embodiments, theformulation reaches a mean Cmax plasma concentration in less than 2hours following administration. In some embodiments, the formulation isa solid dosage formulation comprising 25 mg of rofecoxib, and wherein asingle administration of the formulation to human subjects less than 65years of age achieves a mean Cmax plasma concentration of more than 240ng/ml. In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 300 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 320ng/ml. In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 350 ng/ml.

In some embodiments, the formulation is a solid dosage formulationcomprising 25 mg of rofecoxib, and wherein a single administration ofthe formulation to human subjects less than 65 years of age achieves amean AUC_(0-∞) of more than 4500 h*ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 4700 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 5000h*ng/ml.

In some embodiments, the formulation is a solid dosage formulationcomprising 25 mg of rofecoxib, and wherein a single administration ofthe formulation in human subjects less than 65 years of age reaches amean Cmax plasma concentration of more than 240 ng/ml in less than 3hours following administration with a mean AUC_(0-∞) of more than 4250h*ng/ml.

In certain aspects, the subject matter disclosed herein provides a soliddosage formulation comprising 10 mg to 50 mg of rofecoxib and apharmaceutically acceptable carrier, wherein a single administration ofthe formulation in human subjects less than 65 years of age achieves amean Cmax plasma concentration from 9.8 ng/ml to 16 ng/ml for each 1 mgof rofecoxib in the formulation.

In some embodiments, the formulation achieves a mean Cmax plasmaconcentration from 10 ng/ml to 14 ng/ml for each 1 mg of rofecoxib inthe formulation. In some embodiments, the formulation achieves a meanCmax plasma concentration from 10 ng/ml to 13 ng/ml for each 1 mg ofrofecoxib in the formulation. In some embodiments, the formulationachieves a mean Cmax plasma concentration from 80% to 125% of 12.8ng/ml. In some embodiments, the formulation achieves a mean Cmax plasmaconcentration that is bioequivalent to 12.8 ng/ml. In some embodiments,the formulation achieves a mean Cmax plasma concentration that is 80% to125% of 12.8 ng/ml.

In certain aspects, the subject matter disclosed herein provides a soliddosage formulation comprising 10 mg to 50 mg of rofecoxib and apharmaceutically acceptable carrier, wherein a single administration ofthe formulation in human subjects less than 65 years of age achieves amean AUC_(0-∞) of 170 h*ng/ml to 235 h*ng/ml for each 1 mg of rofecoxibin the formulation.

In some embodiments, the formulation achieves a mean AUC_(0-∞) of 170h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib in the formulation. Insome embodiments, the formulation achieves a mean AUC_(0-∞) of 177h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib in the formulation. Insome embodiments, the formulation achieves a mean AUC_(0-∞) of 180h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib in the formulation. Insome embodiments, the formulation achieves a mean AUC_(0-∞) of 190h*ng/ml to 215 h*ng/ml for each 1 mg of rofecoxib in the formulation.

In certain aspects, the subject matter disclosed herein provides amethod of inhibiting COX-2 in a subject by administering theformulations described herein.

In certain aspects, the subject matter disclosed herein provides amethod of inhibiting COX-2 in a subject by administering a solid dosageformulation comprising 17.5 mg of rofecoxib.

In some embodiments, the formulation is a solid dosage formulationcomprising 17.5 mg of rofecoxib, wherein a single administration of theformulation to human subjects less than 65 years of age achieves a meanCmax that is equal to or greater than that reported by Schwartz, J. I.,et al. Clin. Drug Invent. 2003, 23 (8): 503-509 for a rofecoxib 25 mgtablet. In some embodiments, the formulation is a solid dosageformulation comprising 17.5 mg of rofecoxib, wherein a singleadministration of the formulation to human subjects less than 65 yearsof age achieves a mean Cmax that is equal to or greater than thatreported in the FDA-approved label for VIOXX for a single 25-mg dose ofVIOXX. In some embodiments, the formulation is a solid dosageformulation comprising 20 mg of rofecoxib, where a single administrationof the formulation to human subjects less than 65 years of age achievesa mean AUC_(0-∞) that is equal to or greater than that reported bySchwartz, J. I., et al. Clin. Drug Invent. 2003, 23 (8): 503-509 for arofecoxib 25 mg tablet. In some embodiments, the formulation is a soliddosage formulation comprising 20 mg of rofecoxib, where a singleadministration of the formulation to human subjects less than 65 yearsof age achieves a mean Cmax that is equal to or greater than thatreported by Schwartz, J. I., et al. Clin. Drug Invent. 2003, 23 (8):503-509 for a rofecoxib 25 mg tablet. In some embodiments, theformulation is a solid dosage formulation comprising 20 mg of rofecoxib,wherein a single administration of the formulation to human subjectsless than 65 years of age achieves a mean AUC_(0-∞) that is equal to orgreater than that reported in the FDA-approved label for VIOXX for asingle 25-mg dose of VIOXX. In some embodiments, the formulation is asolid dosage formulation comprising 20 mg of rofecoxib, wherein a singleadministration of the formulation to human subjects less than 65 yearsof age achieves a mean Cmax that is equal to or greater than thatreported in the FDA-approved label for VIOXX for a single 25-mg dose ofVIOXX.

In some embodiments, the patient is age 2 or older.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a patient byadministering the formulations as described herein.

In some embodiments, the human subjects are healthy human subjects. Insome embodiments, the patient is age 2 or older.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever or inflammation in a patient populationcomprising providing a solid dosage formulation comprising 10 mg to 50mg of rofecoxib to the patient population for inhibiting COX-2, whereinthe formulation achieves a mean Cmax plasma concentration of between 80to 125% of 12.8 ng/ml for each 1 mg of rofecoxib in the formulationfollowing single administration of the formulation in the patientpopulation. In some embodiments, the formulation achieves a mean Cmaxplasma concentration that is bioequivalent to 12.8 ng/ml for each 1 mgof rofecoxib in the formulation. In some embodiments, the formulationachieves a mean Cmax plasma concentration that is between 80 to 125% of12.8 ng/ml for each 1 mg of rofecoxib in the formulation.

In some embodiments, the subject matter disclosed herein provides aformulation comprising 12.5 mg to 25 mg of rofecoxib and apharmaceutically acceptable carrier, wherein a single administration ofthe formulation in human female subjects less than 65 years of ageachieves a mean Cmax plasma concentration that is at least 5%, 10%, 15%,20%, 25%, or 30% greater than that achieved following a singleadministration of the formulation to human male subjects less than 65years of age. In some embodiments, the subject matter disclosed hereinprovides a formulation comprising 12.5 mg to 25 mg of rofecoxib and apharmaceutically acceptable carrier, wherein a single administration ofthe formulation in human female subjects less than 65 years of ageachieves a mean AUC_(0-∞) that is at least 5%, 10%, 15%, 20%, 25%, or30% greater than that achieved following a single administration of theformulation to human male subjects less than 65 years of age.

In some embodiments, the subject matter disclosed herein provides aformulation comprising 12.5 mg to 25 mg of rofecoxib and apharmaceutically acceptable carrier, wherein a single administration ofthe formulation in Caucasian subjects less than 65 years of age achievesa mean AUC_(0-∞) that is greater than that achieved following a singleadministration of the formulation to African American subjects less than65 years of age. In some embodiments, the formulation achieves a meanAUC_(0-∞) in Caucasian subjects that is at least 1%, 2%, 5%, 9%, or 10%greater than that achieved following a single administration of theformulation to African American subjects less than 65 years of age.

In some embodiments, the subject matter herein provides a solid dosageformulation comprising 12.5 mg of rofecoxib, wherein the formulationachieves a mean plasma concentration of at least about 0.2 ng/ml, 0.3ng/ml, 0.4 ng/ml, or 0.5 ng/ml at 15 minutes following singleadministration of the formulation to human subjects less than 65 yearsof age. In some embodiments, the subject matter herein provides a soliddosage formulation comprising 12.5 mg of rofecoxib, wherein theformulation achieves an arithmetic mean plasma concentration of at leastabout 0.8 ng/ml, 0.9 ng/ml, or 1.0 ng/ml at 15 minutes following singleadministration of the formulation to human subjects less than 65 yearsof age. In some embodiments, the subject matter herein provides a soliddosage formulation comprising 17.5 mg of rofecoxib, wherein theformulation achieves a mean plasma concentration of at least about 0.3ng/ml, 0.4 ng/ml, 0.5 ng/ml, or 0.6 ng/ml at 15 minutes following singleadministration of the formulation to human subjects less than 65 yearsof age. In some embodiments, the subject matter herein provides a soliddosage formulation comprising 17.5 mg of rofecoxib, wherein theformulation achieves an arithmetic mean plasma concentration of at leastabout 1.8 ng/ml, 2.0 ng/ml, 2.2 ng/ml, or 2.4 ng/ml at 15 minutesfollowing single administration of the formulation to human subjectsless than 65 years of age. In some embodiments, the subject matterherein provides a solid dosage formulation comprising 20 mg ofrofecoxib, wherein the formulation achieves a mean plasma concentrationof at least about 0.8 ng/ml, 0.9 ng/ml, 1.0 ng/ml, 1.1 ng/ml, or 1.16ng/ml at 15 minutes following single administration of the formulationto human subjects less than 65 years of age. In some embodiments, thesubject matter herein provides a solid dosage formulation comprising 20mg of rofecoxib, wherein the formulation achieves an arithmetic meanplasma concentration of at least about 4.6 ng/ml, 5.0 ng/ml, 5.4 ng/ml,or 5.7 ng/ml at 15 minutes following single administration of theformulation to human subjects less than 65 years of age. In someembodiments, the subject matter herein provides a solid dosageformulation comprising a solid dosage formulation comprising 25 mg ofrofecoxib, wherein the formulation achieves a mean plasma concentrationof at least about 1.0 ng/ml, 1.1 ng/ml, 1.2 ng/ml, or 1.3 ng/ml at 15minutes following single administration of the formulation to humansubjects less than 65 years of age. In some embodiments, the subjectmatter herein provides a solid dosage formulation comprising a soliddosage formulation comprising 25 mg of rofecoxib, wherein theformulation achieves an arithmetic mean plasma concentration of at leastabout 4.6 ng/ml, 5.0 ng/ml, 5.4 ng/ml, or 5.6 ng/ml at 15 minutesfollowing single administration of the formulation to human subjectsless than 65 years of age. In some embodiments, the subject matterherein provides a solid dosage formulation comprising 12.5 mg ofrofecoxib, wherein the formulation achieves a mean plasma concentrationof at least about 27 ng/ml, 29 ng/ml, 31 ng/ml, or 33 ng/ml at 45minutes following single administration of the formulation to humansubjects less than 65 years of age. In some embodiments, the subjectmatter herein provides a solid dosage formulation comprising 12.5 mg ofrofecoxib, wherein the formulation achieves an arithmetic mean plasmaconcentration of at least about 45 ng/ml, 48 ng/ml, 51 ng/ml, 54 ng/ml,or 56 ng/ml at 45 minutes following single administration of theformulation to human subjects less than 65 years of age. In someembodiments, the subject matter herein provides a solid dosageformulation comprising a solid dosage formulation comprising 17.5 mg ofrofecoxib, wherein the formulation achieves a mean plasma concentrationof at least about 45 ng/ml, 47 ng/ml, 49 ng/ml, or 51 ng/ml at 45minutes following single administration of the formulation to humansubjects less than 65 years of age. In some embodiments, the subjectmatter herein provides a solid dosage formulation comprising a soliddosage formulation comprising 17.5 mg of rofecoxib, wherein theformulation achieves an arithmetic mean plasma concentration of at leastabout 74 ng/ml, 79 ng/ml, 84 ng/ml, 89 ng/ml, or 93 ng/ml at 45 minutesfollowing single administration of the formulation to human subjectsless than 65 years of age. In some embodiments, the subject matterherein provides a solid dosage formulation comprising 20 mg ofrofecoxib, wherein the formulation achieves a mean plasma concentrationof at least about 58 ng/ml, 62 ng/ml, 66 ng/ml, 70 ng/ml, or 72 ng/ml at45 minutes following single administration of the formulation to humansubjects less than 65 years of age. In some embodiments, the subjectmatter herein provides a solid dosage formulation comprising 20 mg ofrofecoxib, wherein the formulation achieves an arithmetic mean plasmaconcentration of at least about 112 ng/ml, 116 ng/ml, or 121 ng/ml at 45minutes following single administration of the formulation to humansubjects less than 65 years of age. In some embodiments, the subjectmatter herein provides a solid dosage formulation comprising 25 mg ofrofecoxib, wherein the formulation achieves a mean plasma concentrationof at least about 78 ng/ml, 85 ng/ml, 92 ng/ml, or 97 ng/ml, at 45minutes following single administration of the formulation to humansubjects less than 65 years of age. In some embodiments, the subjectmatter herein provides a solid dosage formulation comprising 25 mg ofrofecoxib, wherein the formulation achieves an arithmetic mean plasmaconcentration of at least about 133 ng/ml, 139 ng/ml, 145 ng/ml, 151ng/ml, or 159 ng/ml at 45 minutes following single administration of theformulation to human subjects less than 65 years of age.

In some embodiments, the formulation and methods set forth hereinachieve the recited median time to Cmax, mean Cmax plasma concentration,and mean AUC_(0-∞) values following the administration of theformulation to human subjects less than 65 years of age in a single dosepharmacokinetic study. In any of the embodiments described herein, thehuman subjects may be in a fasting state. In any of the embodimentsdescribed herein, the human subjects may be less than 60 years of age.In any of the embodiments described herein, the human subjects may be apopulation of healthy adults less than 65 years or 60 years of age.

BRIEF DESCRIPTION OF FIGURES

The patent application contains at least one drawing in color.

FIGS. 1A-B show two embodiments of the composition of a 25-mg rofecoxibtablet. FIG. 1A shows the composition of a 25-mg rofecoxib tablet inprototype batches 1-8. FIG. 1B shows the composition of a 25-mgrofecoxib tablet.

FIG. 2 shows process conditions for Process A₁₋₃ in manufacturing ofbatches 1-4.

FIGS. 3A-B show dissolution profiles of rofecoxib tablets, batches 1 and2. FIG. 3A shows dissolution of rofecoxib tablets in 0.1N HCl. FIG. 3Bshows dissolution of rofecoxib tablets in at least 2% SDS.

FIGS. 4A-B show dissolution profiles of rofecoxib tablets, batches 3 and4. FIG. 4A shows dissolution of rofecoxib tablets in 0.1N HCl. FIG. 4Bshows dissolution of rofecoxib tablets in at least 2% SDS.

FIG. 5 shows process conditions for batches 5-8.

FIGS. 6A-B shows dissolution profiles for Process B₁ in manufacturingbatches 5-8. FIG. 6A shows dissolution of rofecoxib tablets in batches 5and 6. FIG. 6B shows dissolution of rofecoxib tablets in batches 7 and8.

FIG. 7 shows dissolution profiles for batches 5 and 6

FIG. 8 shows composition of 25-mg rofecoxib tablet in prototype batches5-6.

FIG. 9 shows processes description for the manufacture of prototype25-mg rofecoxib tablets.

FIGS. 10A-B show a flow diagram for rofecoxib tablet manufacturingProcess A₁. FIG. 10A shows manufacture of rofecoxib granules. FIG. 10Bshows manufacture of rofecoxib tablets.

FIGS. 11A-B show a flow diagram for rofecoxib tablet manufacturingProcess A₂. FIG. 11A shows manufacture of rofecoxib granules. FIG. 11Bshows manufacture of rofecoxib tablets.

FIGS. 12A-B show a flow diagram for rofecoxib tablet manufacturingProcess A₃. FIG. 12A shows manufacture of rofecoxib granules. FIG. 12Bshows manufacture of rofecoxib tablets.

FIGS. 13A-B show a flow diagram for rofecoxib tablet manufacturingProcess B₁. FIG. 13A shows manufacture of rofecoxib granules. FIG. 13Bshows manufacture of rofecoxib tablets.

FIG. 14 shows granule size distribution across rofecoxib batches.

FIGS. 15A-B show dissolution of rofecoxib tablets. FIG. 15A showsdissolution of rofecoxib tablets in 0.1N HCl for batches 1 and 2. FIG.15B shows dissolution of rofecoxib tablets in at least 2% SDS forbatches 1 and 2.

FIGS. 16A-B show dissolution of rofecoxib tablets. FIG. 16A showsdissolution of rofecoxib tablets in 0.1N HCl for batches 3 and 4. FIG.16B shows dissolution of rofecoxib tablets in at least 2% SDS forbatches 3 and 4.

FIG. 17 shows dissolution versus percent water used in granulation.

FIG. 18 shows granule size distribution across rofecoxib batches.

FIGS. 19A-B show dissolution of rofecoxib tablets. FIG. 19A showsdissolution of rofecoxib tablets in at least 2% SDS for batches 5 and 6.FIG. 19B shows dissolution of rofecoxib tablets in at least 2% SDS forbatches 7 and 8.

FIGS. 20A-B show dissolution of rofecoxib tablets. FIG. 20A showsdissolution of rofecoxib tablets in at least 2% SDS for batches 5 and 6.FIG. 20B shows dissolution of rofecoxib tablets in at least 2% SDS forbatches 5 and 6.

FIG. 21 shows granule size distribution across rofecoxib batches.

FIGS. 22A-B show dissolution of rofecoxib tablets. FIG. 22A showsdissolution of rofecoxib tablets in at least 2% SDS for batches 5 and 6at 75 rpm. FIG. 22B shows dissolution of rofecoxib tablets in at least2% SDS for batches 5 and 6 at 50 rpm.

FIGS. 23A-B show dissolution of rofecoxib tablets. FIG. 23A showsdissolution of rofecoxib tablets in 1.5% SDS for batches 5 and 6 at 75rpm. FIG. 23B shows dissolution of rofecoxib tablets in 1.5% SDS forbatches 5 and 6 at 50 rpm.

FIGS. 24A-B show dissolution of rofecoxib tablets. FIG. 24A showsdissolution of rofecoxib tablets in 1.0% SDS for batches 5 and 6 at 75rpm. FIG. 24B shows dissolution of rofecoxib tablets in 1.0% SDS forbatches 5 and 6 at 50 rpm.

FIG. 25 shows a summary of fasted AUC_(0-∞) and Cmax in the PK 101(Example 4) pharmacokinetic study.

FIG. 26 shows a summary of treatment-emergent adverse events (101 studyonly).

FIG. 27 shows mean fasted concentration versus scheduled time (101 studyonly).

FIG. 28 shows an analysis of AUC_(0-∞) and Cmax compared to historicaldata (101 study only).

FIG. 29 shows a scatterplot of AUC_(0-∞) by age (101 study only).

FIG. 30 shows a scatterplot of Cmax by age (101 study only).

FIG. 31 shows extrapolated pharmacokinetic AUC and Cmax values fordosages other than 25 mg of rofecoxib.

FIG. 32 shows a summary of subject disposition for all screened subjects(102 study only).

FIG. 33 shows demographic and baseline characteristics—safety (102 studyonly).

FIG. 34 shows demographic and baseline characteristics—safety, BMI (102study only).

FIG. 35 shows demographic and baseline characteristics—PK (102 studyonly).

FIG. 36 shows demographic and baseline characteristics—PK, BMI (102study only).

FIG. 37 shows a summary of fasted plasma rofecoxib concentration(ng/mL)—PK, time points 0.00, 0.25, 0.5 hr (102 study only).

FIG. 38 shows a summary of fasted plasma rofecoxib concentration(ng/mL)—PK, time points 0.75, 1, 1.5 hr (102 study only).

FIG. 39 shows a summary of fasted plasma rofecoxib concentration(ng/mL)—PK, time points 2, 3, 4 hr (102 study only).

FIG. 40 shows a summary of fasted plasma rofecoxib concentration(ng/mL)—PK, time points 5, 6, 7.5 hr (102 study only).

FIG. 41 shows a summary of fasted plasma rofecoxib concentration(ng/mL)—PK, time points 9, 12, 15 hr (102 study only).

FIG. 42 shows a summary of fasted plasma rofecoxib concentration(ng/mL)—PK, time points 18, 21, 24 hr (102 study only).

FIG. 43 shows a summary of fasted plasma rofecoxib concentration(ng/mL)—PK, time points 27, 30, 33 hr (102 study only).

FIG. 44 shows a summary of fasted plasma rofecoxib concentration(ng/mL)—PK, time points 36, 39, 42 hr (102 study only).

FIG. 45 shows a summary of fasted plasma rofecoxib concentration(ng/mL)—PK, time points 48, 52, 60 hr (102 study only).

FIG. 46 shows a summary of fasted plasma rofecoxib concentration(ng/mL)—PK, time points 72, 96, 120 hr (102 study only).

FIG. 47 shows a summary of fasted AUC_(0-∞) and Cmax (101 and 102studies)—PK.

FIG. 48 shows a summary of fasted AUC_(0-∞) (102 study only)—PK.

FIG. 49 shows a summary of fasted C_(max) (102 study only)—PK.

FIG. 50 shows a summary of fasted AUC_(0-∞) and C_(max) by gender (102study only)—12.5 mg PK.

FIG. 51 shows a summary of fasted AUC_(0-∞) and C_(max) by gender (102study only)—17.5 mg PK.

FIG. 52 shows a summary of fasted AUC_(0-∞) and C_(max) by gender (102study only)—20 mg PK.

FIG. 53 shows a summary of fasted AUC_(0-∞) and C_(max) by gender (102study only)—25 mg PK.

FIG. 54 shows a summary of fasted AUC_(0-∞) and C_(max) by age (102study only)—12.5 mg PK.

FIG. 55 shows a summary of fasted AUC_(0-∞) and C_(max) by age (102study only)—17.5 mg PK.

FIG. 56 shows a summary of fasted AUC_(0-∞) and C_(max) by age (102study only)—20 mg PK.

FIG. 57 shows a summary of fasted AUC_(0-∞) and C_(max) by age (102study only)—25 mg PK.

FIG. 58 shows a summary of fasted AUC_(0-∞) and C_(max) by race (102study only)—12.5 mg PK.

FIG. 59 shows a summary of fasted AUC_(0-∞) and C_(max) by race (102study only)—17.5 mg PK.

FIG. 60 shows a summary of fasted AUC_(0-∞) and C_(max) by race (102study only)—20 mg PK.

FIG. 61 shows a summary of fasted AUC_(0-∞) and C_(max) by race (102study only)—25 mg PK.

FIG. 62 shows a summary of fasted AUC_(0-∞) and C_(max) by body weight(102 study only)—12.5 mg PK.

FIG. 63 shows a summary of fasted AUC_(0-∞) and C_(max) by body weight(102 study only)—17.5 mg PK.

FIG. 64 shows a summary of fasted AUC_(0-∞) and C_(max) by body weight(102 study only)—20 mg PK.

FIG. 65 shows a summary of fasted AUC_(0-∞) and C_(max) by body weight(102 study only)—25 mg PK.

FIG. 66 shows a summary of fasted AUC_(0-∞) and C_(max) by ethnicity(102 study only)—12.5 mg PK.

FIG. 67 shows a summary of fasted AUC_(0-∞) and C_(max) by ethnicity(102 study only)—17.5 mg PK.

FIG. 68 shows a summary of fasted AUC_(0-∞) and C_(max) by ethnicity(102 study only)—20 mg PK.

FIG. 69 shows a summary of fasted AUC_(0-∞) and C_(max) by ethnicity(102 study only)—25 mg PK.

FIG. 70 shows a sensitivity analysis of fasted AUC_(0-∞) and Cmaxcompared to historical data—PK (102 study only).

FIG. 71 shows a summary of fasted T_(max) and t_(1/2) (101 and 102studies combined)—PK.

FIG. 72 shows a summary of fasted CL/F and V_(d)/F (102 study only)—PK.

FIG. 73 shows an exploratory analysis of fasted AUC_(0-∞) and C_(max) toestimate the dose that yields values equal to those observed in thehistorical data (102 study only)—PK.

FIG. 74 shows a summary of treatment-emergent adverse events—safety (102study only).

FIG. 75 shows incidence of treatment-emergent adverse events by systemorgan class and preferred term—safety (102 study only).

FIG. 76 shows incidence of related treatment-emergent adverse events bysystem organ class and preferred term—safety (102 study only).

FIG. 77 shows incidence of serious treatment-emergent adverse events bysystem organ class and preferred term—safety (102 study only).

FIG. 78 shows incidence of treatment adverse events leading to studydiscontinuation by system organ class and preferred term (102 studyonly).

FIG. 79 shows incidence of treatment-emergent adverse events by systemorgan class, preferred term, and severity—safety (102 study only).

FIG. 80 shows arithmetic mean (SD) fasted concentration versus scheduledtime profiles on the linear scale (102 study only).

FIG. 81 shows TRM-201 12.5 mg arithmetic mean (SD) fasted concentrationversus scheduled time profiles on the linear scale (102 study only).

FIG. 82 shows TRM-201 17.5 mg arithmetic mean (SD) fasted concentrationversus scheduled time profiles on the linear scale (102 study only).

FIG. 83 shows TRM-201 20 mg arithmetic mean (SD) fasted concentrationversus scheduled time profiles on the linear scale (102 study only).

FIG. 84 shows TRM-201 25 mg arithmetic mean (SD) fasted concentrationversus scheduled time profiles on the linear scale (102 study only).

FIG. 85 shows arithmetic mean fasted concentration versus scheduled timeprofiles on the linear scale (102 study only).

FIG. 86 shows geometric mean (SD) fasted concentration versus scheduledtime profile on the semi-logarithmic scale (102 study only).

FIG. 87 shows TRM-201 12.5 mg geometric mean (SD) fasted concentrationversus scheduled time profiles on the semi-logarithmic scale (102 studyonly).

FIG. 88 shows TRM-201 17.5 mg geometric mean (SD) fasted concentrationversus scheduled time profiles on the semi-logarithmic scale (102 studyonly).

FIG. 89 shows TRM-201 20 mg geometric mean (SD) fasted concentrationversus scheduled time profiles on the semi-logarithmic scale (102 studyonly).

FIG. 90 shows TRM-201 25 mg geometric mean (SD) fasted concentrationversus scheduled time profiles on the semi-logarithmic scale (102 studyonly).

FIG. 91 shows geometric mean fasted concentration versus scheduled timeprofiles on the semi-logarithmic scale (102 study only).

FIG. 92 shows a scatterplot of fasted AUC_(0-∞) by age (102 study only).

FIG. 93 shows a scatterplot of fasted AUC_(0-∞) by race (102 studyonly).

FIG. 94 shows a scatterplot of fasted AUC_(0-∞) by body weight (102study only).

FIG. 95 shows a scatterplot of fasted AUC_(0-∞) by BMI (102 study only).

FIG. 96 shows a scatterplot of fasted C_(max) by age (102 study only).

FIG. 97 shows a scatterplot of fasted C_(max) by race (102 study only).

FIG. 98 shows a scatterplot of fasted C_(max) by body weight (102 studyonly).

FIG. 99 shows a scatterplot of fasted C_(max) by BMI (102 study only).

FIG. 100 shows a scatterplot of fasted AUC_(0-∞) and C_(max)(dose-adjusted on raw scale) (102 study only).

FIG. 101 shows a scatterplot of fasted AUC_(0-∞) and C_(max) (notdose-adjusted on natural-log scale) (102 study only).

FIGS. 102A-B show a boxplot of fasted AUC_(0-∞) and Cmax, respectively.

FIG. 103 shows a comparison of the mean plasma concentration (ng/L)versus time for TRM-201 20 mg and the 25 mg “VIOXX” tablet and oralsuspension reported in Schwartz, J. I., et al. Clin. Drug Invent. 2003,23 (8): 503-509.

FIG. 104 shows a comparison of the mean plasma concentration (ng/L)versus time for TRM-201 20 mg and the 25 mg “VIOXX” tablet reported inSchwartz, J. I., et al. Clin. Drug Invent. 2003, 23 (8): 503-509.

DETAILED DESCRIPTION Definitions

The following are definitions of terms used in the presentspecification. The initial definition provided for a group or termherein applies to that group or term throughout the presentspecification individually or as part of another group, unless otherwiseindicated. Unless otherwise defined, all technical and scientific termsused herein have the same meaning as commonly understood by one ofordinary skill in the art.

As used herein, “dissolution rate” refers to the proportion of drugwhich enters a solution in a given amount of time.

As used herein, “rofecoxib” refers to the active ingredient4-[4-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone or apharmaceutically acceptable salt, solvate, or co-crystal thereof. Therofecoxib as described herein may be in amorphous or crystalline form.The purity of rofecoxib is determined as a percent (%) area basis,typically as quantified by analytical chromatography, such as usingHPLC, UHPLC or UPLC.

In some embodiments, the highly pure rofecoxib comprises less than orequal to about 0.10%, 0.075%, 0.050%, 0.025%, 0.020%, or 0.001% areabasis total impurities. In some embodiments, the highly pure rofecoxibcomprises less than about 0.10%, 0.05%, 0.02%, or 0.01% of4-[4-(methylsulphonyl)phenyl]-3-phenyl-2,5-furandione. In someembodiments, the highly pure rofecoxib comprises less than about 0.10%,0.05%, 0.02%, or 0.01% of4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some embodiments,the highly pure rofecoxib comprises less than about 0.10%, 0.05%, 0.02%,or 0.01% of 4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In someembodiments, the highly pure rofecoxib comprises less than about 0.10%,0.05%, 0.02%, or 0.01% of4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone.

As used herein, “highly pure” means, with respect to an activeingredient, having less than or equal to about 0.10% area basis totalimpurities.

As used herein, “substantially pure” means, with respect to an activeingredient, having less than or equal to about 0.50% area basis totalimpurities.

As used herein, “essentially free” means, with respect to an impurity,having less than about 0.10% area basis of the impurity.

As used herein, “free of” means, with respect to an impurity having anamount of the impurity that is below the limitation of detection i.e.less than 0.02% area basis of the impurity.

The term “disintegrant” as used herein includes auxiliary agents whichpromote the disintegration of tablets or granulates. upon contact withliquids.

The singular forms “a”, “an” and “the” include plural reference unlessthe context clearly dictates otherwise. The use of the word “a” or “an”when used in conjunction with the term “comprising” in the claims and/orthe specification may mean “one,” but it is also consistent with themeaning of “one or more,” “at least one,” and “one or more than one.”

As used herein the term “about” is used herein to mean approximately,roughly, around, or in the region of. When the term “about” is used inconjunction with a numerical range, it modifies that range by extendingthe boundaries above and below the numerical values set forth. Ingeneral, the term “about” is used herein to modify a numerical valueabove and below the stated value by a variance of 20 percent up or down(higher or lower).

The term “pharmaceutically acceptable salt,” as used herein, refers tothe relatively non-toxic, inorganic and organic acid salts of compoundsof the subject matter described herein.

As used herein, the term “subject” refers to a vertebrate animal. In oneembodiment, the subject is a mammal or a mammalian species. In oneembodiment, the subject is a human. In one embodiment, the subject is ahealthy human adult. In other embodiments, the subject is a non-humanvertebrate animal, including, without limitation, non-human primates,laboratory animals, livestock, racehorses, domesticated animals, andnon-domesticated animals. In one embodiment, the term “human subjects”means a population of healthy human adults. In one embodiment, thesubject is a human that is not hepatically impaired.

As used herein, the term “patient” refers to a human or animal.

The term “mammal” includes, but is not limited to, a human, mouse, rat,guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as amonkey, chimpanzee, baboon or rhesus. In one embodiment, the mammal is ahuman.

As used herein, the term “effective amount” means an amount of apharmaceutically active compound, i.e. a drug active, e.g. a quinolonecarboxylic acid antimicrobial agent or pharmaceutically acceptable saltor ester thereof, given to a recipient patient sufficient to elicitbiological activity, for example, anti-infective activity, e.g.,anti-microbial activity.

As used herein, the term “a mean” refers to a geometric mean unlessexpressly indicated otherwise. The pharmacokinetic parameters such as “amean Cmax” or “a mean AUC” refers to the geometric mean value of a Cmaxor an AUC, unless expressly indicated otherwise.

The expression “bioequivalent” or “bioequivalence” is a term of art andis intended to be defined in accordance with 21 C.F.R. § 320.1 andprevailing guidelines from the FDA. Bioequivalence of differentformulation of the same drug substance involves equivalence with respectto the rate and extent of drug absorption. The extent and rate ofabsorption of the test formulation is compared to a referenceformulation in order to determine whether the two formulations arebioequivalent. In practice, two products are considered bioequivalent ifthe 90% confidence interval of the ratio of a log-transformed exposuremeasure (AUC and/or Cmax) falls completely within the range 80-125%.

Compositions of the Present Subject Matter

In certain aspects, the subject matter disclosed herein provides a soliddosage formulation comprising 17.5 mg of rofecoxib and apharmaceutically acceptable carrier.

In some embodiments, the rofecoxib formulation reaches a median time toCmax plasma concentration in 4 hours or less following a singleadministration of the formulation to human subjects less than 65 yearsof age. In some embodiments, the rofecoxib formulation reaches a mediantime to Cmax plasma concentration in 3.5 hours or less following asingle administration of the formulation to human subjects less than 65years of age. In some embodiments, the rofecoxib formulation reaches amedian time to Cmax plasma concentration in 3 hours or less following asingle administration of the formulation to human subjects less than 65years of age. In some embodiments, the rofecoxib formulation reaches amedian time to Cmax plasma concentration in 2.5 hours or less followinga single administration of the formulation to human subjects less than65 years of age.

In certain aspects, the subject matter disclosed herein provides a soliddosage formulation comprising 17.5 mg of rofecoxib and apharmaceutically acceptable carrier, wherein the formulation achieves amean Cmax plasma concentration of more than 100 ng/ml following a singleadministration of the formulation to human subjects less than 65 yearsof age.

In some embodiments, the rofecoxib formulation achieves a mean Cmaxplasma concentration of more than 150 ng/ml, 167 ng/ml, or 190 ng/ml. Insome embodiments, the rofecoxib formulation achieves a mean Cmax plasmaconcentration of more than 200 ng/ml. In some embodiments, the rofecoxibformulation achieves a mean Cmax plasma concentration of more than 220ng/ml. In some embodiments, the rofecoxib formulation achieves a meanCmax plasma concentration of more than 250 ng/ml.

In certain aspects, the subject matter disclosed herein provides a soliddosage formulation comprising 17.5 mg of rofecoxib and apharmaceutically acceptable carrier, wherein the formulation achieves amean AUC_(0-∞) of more than 1750 h*ng/ml following a singleadministration of the formulation to human subjects less than 65 yearsof age.

In some embodiments, the rofecoxib formulation achieves a mean AUC_(0-∞)of more than 2000 h*ng/ml following a single administration of theformulation to human subjects less than 65 years of age. In someembodiments, the rofecoxib formulation achieves a mean AUC_(0-∞) of morethan 2500 h*ng/ml following a single administration of the formulationto human subjects less than 65 years of age. In some embodiments, therofecoxib formulation achieves a mean AUC_(0-∞) of more than 3000h*ng/ml following a single administration of the formulation to humansubjects less than 65 years of age. In some embodiments, the rofecoxibformulation achieves a mean AUC_(0-∞) of more than 3100 h*ng/mlfollowing a single administration of the formulation to human subjectsless than 65 years of age. In some embodiments, the rofecoxibformulation achieves a mean AUC_(0-∞) of more than 3500 h*ng/mlfollowing a single administration of the formulation to human subjectsless than 65 years of age.

In some embodiments, the rofecoxib formulation further comprises agranular component and an extragranular component, wherein the granularcomponent comprises an intragranular component comprising the rofecoxiband one or more disintegrants, and wherein the extragranular componentcomprises one or more disintegrants. In some embodiments, the rofecoxibin the formulation has a d90 particle size from about 10-12 μm, a d50particle size from about 3-4 μm, and a d10 particle size from about0.5-1.0 μm.

In certain aspects, the subject matter disclosed herein provides a soliddosage formulation comprising 20 mg of rofecoxib and a pharmaceuticallyacceptable carrier.

In some embodiments, the formulation reaches a median time to Cmaxplasma concentration in 4 hours or less following a singleadministration of the formulation to human subjects less than 65 yearsof age. In some embodiments, the formulation reaches a median time toCmax plasma concentration in 3 hours or less following administration.In some embodiments, the formulation reaches a mean Cmax plasmaconcentration in less than 3 hours following administration. In someembodiments, the formulation reaches a median time to Cmax plasmaconcentration in 2.5 hours or less following administration.

In certain aspects, the subject matter disclosed herein provides a soliddosage formulation comprising 20 mg of rofecoxib and a pharmaceuticallyacceptable carrier, wherein the formulation achieves a mean Cmax plasmaconcentration of more than 150 ng/ml following a single administrationof the formulation to human subjects less than 65 years of age.

In some embodiments, the rofecoxib formulation achieves a mean Cmaxplasma concentration of more than 191 ng/ml, 200 ng/ml, 215 ng/ml, or225 ng/ml following a single administration of the formulation to humansubjects less than 65 years of age. In some embodiments, the rofecoxibformulation achieves a mean Cmax plasma concentration of more than 250ng/ml following a single administration of the formulation to humansubjects less than 65 years of age. In some embodiments, the rofecoxibformulation achieves a mean Cmax plasma concentration of more than 258ng/ml following a single administration of the formulation to humansubjects less than 65 years of age. In some embodiments, the rofecoxibformulation achieves a mean Cmax plasma concentration of more than 300ng/ml following a single administration of the formulation to humansubjects less than 65 years of age.

In certain aspects, the subject matter disclosed herein provides a soliddosage formulation comprising 20 mg of rofecoxib and a pharmaceuticallyacceptable carrier, wherein the formulation achieves a mean AUC_(0-∞) ofmore than 2000 h*ng/ml following a single administration of theformulation to human subjects less than 65 years of age.

In some embodiments, the formulation achieves a mean AUC_(0-∞) of morethan 2500 h*ng/ml following a single administration of the formulationto human subjects less than 65 years of age. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 3000 h*ng/mlfollowing a single administration of the formulation to human subjectsless than 65 years of age. In some embodiments, the formulation achievesa mean AUC_(0-∞) of more than 3400 h*ng/ml following a singleadministration of the formulation to human subjects less than 65 yearsof age. In some embodiments, the formulation achieves a mean AUC_(0-∞)of more than 3500 h*ng/ml following a single administration of theformulation to human subjects less than 65 years of age. In someembodiments, the rofecoxib formulation achieves a mean Cmax plasmaconcentration within 80% to 125% of 259 ng/ml and a mean AUC_(0-∞)within 80% to 125% of 3550 h*ng/ml. In some embodiments, the rofecoxibformulation achieves a mean plasma AUC_(0-∞) of about 2840-4438 h*ng/mland a mean plasma Cmax of about 207-324 ng/ml following oraladministration of a single dose of the formulation to a population ofhealthy adults less than 65 years of age in a fasted state. In someembodiments, the population of healthy adults are less than 60 years ofage.

In some embodiments, the formulation further comprises a granularcomponent and an extragranular component, wherein the granular componentcomprises an intragranular component comprising the rofecoxib and one ormore disintegrants, and wherein the extragranular component comprisesone or more disintegrants. In some embodiments, the rofecoxib in theformulation has a d90 particle size from about 10-12 μm, a d50 particlesize from about 3-4 μm, and a d10 particle size from about 0.5-1.0 μm.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 25 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof, wherein the formulationachieves a mean Cmax plasma concentration in less than 3 hours followinga single administration of the formulation to human subjects less than65 years of age.

In some embodiments, the rofecoxib formulation achieves a median time toCmax plasma concentration in 2.5 hours or less following administrationof the formulation to human subjects less than 65 years of age.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 25 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof, wherein the formulationachieves a mean Cmax plasma concentration of more than 250 ng/mlfollowing a single administration of the formulation to human subjectsless than 65 years of age.

In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 300 ng/ml following administration of theformulation to human subjects less than 65 years of age. In someembodiments, the formulation achieves a mean Cmax plasma concentrationof more than 320 ng/ml following administration of the formulation tohuman subjects less than 65 years of age. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 350ng/ml following administration of the formulation to human subjects lessthan 65 years of age.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 25 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof, wherein the formulationachieves a mean AUC_(0-∞) of more than 4250 h*ng/ml following a singleadministration of the formulation to human subjects less than 65 yearsof age.

In some embodiments, the formulation achieves a mean AUC_(0-∞) of morethan 4500 h*ng/ml following administration of the formulation to humansubjects less than 65 years of age. In some embodiments, the formulationachieves a mean AUC_(0-∞) of more than 4700 h*ng/ml followingadministration of the formulation to human subjects less than 65 yearsof age. In some embodiments, the formulation achieves a mean AUC_(0-∞)of more than 5000 h*ng/ml following administration of the formulation tohuman subjects less than 65 years of age. In some embodiments, theformulation further comprises a granular component and an extragranularcomponent, wherein the granular component comprises an intragranularcomponent comprising the rofecoxib and one or more disintegrants, andwherein the extragranular component comprises one or more disintegrants.

In some embodiments, the rofecoxib in the formulation has a d90 particlesize from about 10-12 μm, a d50 particle size from about 3-4 μm, and ad10 particle size from about 0.5-1.0 μm.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 25 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof, wherein a singleadministration of the formulation to human subjects achieves a mean Cmaxplasma concentration of more than 240 ng/ml in less than 3 hoursfollowing administration with a mean AUC_(0-∞) of more than 4250h*ng/ml.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 17.5 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof.

In some embodiments, the rofecoxib formulation achieves a median time toCmax plasma concentration in 4 hours or less following a singleadministration of the formulation to human subjects less than 65 yearsof age. In some embodiments, the rofecoxib formulation achieves a mediantime to Cmax plasma concentration in 3.5 hours or less followingadministration. In some embodiments, the rofecoxib formulation achievesa median time to Cmax plasma concentration in 3 hours or less followingadministration. In some embodiments, the rofecoxib formulation achievesa median time to Cmax plasma concentration in 2.5 hours or lessfollowing administration.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 17.5 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof, wherein a singleadministration of the formulation to human subjects less than 65 yearsof age achieves a mean Cmax plasma concentration of more than 100 ng/ml.

In some embodiments, the rofecoxib formulation achieves a mean Cmaxplasma concentration of more than 150 ng/ml, 167 ng/ml, or 190 ng/ml. Insome embodiments, the rofecoxib formulation achieves a mean Cmax plasmaconcentration of more than 200 ng/ml. In some embodiments, the rofecoxibformulation achieves a mean Cmax plasma concentration of more than 220ng/ml. In some embodiments, the rofecoxib formulation achieves a meanCmax plasma concentration of more than 250 ng/ml.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 17.5 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof, wherein a singleadministration of the formulation to human subjects less than 65 yearsof age achieves a mean AUC_(0-∞) of more than 1750 h*ng/ml.

In some embodiments, the rofecoxib formulation achieves a mean AUC_(0-∞)of more than 2000 h*ng/ml. In some embodiments, the rofecoxibformulation achieves a mean AUC_(0-∞) of more than 2500 h*ng/ml. In someembodiments, the rofecoxib formulation achieves a mean AUC_(0-∞) of morethan 3000 h*ng/ml. In some embodiments, the rofecoxib formulationachieves a mean AUC_(0-∞) of more than 3100 h*ng/ml. In someembodiments, the rofecoxib formulation achieves a mean AUC_(0-∞) of morethan 3500 h*ng/ml.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 17.5 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof, wherein a singleadministration of the formulation to human subjects less than 65 yearsof age achieves a mean Cmax plasma concentration within 80% to 125% of224 ng/ml.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 17.5 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof, wherein the formulationreaches a Cmax plasma concentration of least 170 ng/ml in the subject.

In some embodiments, the formulation reaches a Cmax plasma concentrationlevel of at least 175 ng/ml. In some embodiments, the formulationreaches a Cmax plasma concentration level of at least 180 ng/ml. In someembodiments, the formulation reaches a Cmax plasma concentration levelof at least 185 ng/ml. In some embodiments, the formulation reaches aCmax plasma concentration level of at least 190 ng/ml.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 17.5 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof, wherein the formulationreaches an AUC_(0-∞) of more than 2600 h*ng/ml in the subject.

In some embodiments, the rofecoxib formulation reaches an AUC_(0-∞) ofmore than 2750 h*ng/ml. In some embodiments, the rofecoxib formulationreaches an AUC_(0-∞) of more than 2900 h*ng/ml. In some embodiments, therofecoxib formulation reaches an AUC_(0-∞) of more than 3050 h*ng/ml. Insome embodiments, the rofecoxib formulation reaches an AUC_(0-∞) of morethan 3200 h*ng/ml. In some embodiments, the rofecoxib formulationreaches an AUC_(0-∞) of more than 3350 h*ng/ml.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 20 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof.

In some embodiments, the rofecoxib formulation achieves a median time toCmax plasma concentration in 4 hours or less following a singleadministration of the formulation to human subjects. In someembodiments, the rofecoxib formulation achieves a median time to Cmaxplasma concentration in 3.5 hours or less following administration. Insome embodiments, the rofecoxib formulation achieves a median time toCmax plasma concentration in 3 hours or less following administration.In some embodiments, the rofecoxib formulation achieves a median time toCmax plasma concentration in 2.5 hours or less following administration.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 20 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof, wherein a singleadministration of the formulation to human subjects less than 65 yearsof age achieves a mean Cmax plasma concentration of more than 150 ng/ml.

In some embodiments, the rofecoxib formulation achieves a mean Cmaxplasma concentration of more than 191 ng/ml, 200 ng/ml, 215 ng/ml, or225 ng/ml. In some embodiments, the rofecoxib formulation achieves amean Cmax plasma concentration of more than 250 ng/ml. In someembodiments, the rofecoxib formulation achieves a mean Cmax plasmaconcentration of more than 258 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 300ng/ml.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 20 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof, wherein a singleadministration of the formulation to human subjects less than 65 yearsof age achieves a mean AUC_(0-∞) of more than 2000 h*ng/ml.

In some embodiments, the rofecoxib formulation achieves a mean AUC_(0-∞)of more than 2500 h*ng/ml. In some embodiments, the rofecoxibformulation achieves a mean AUC_(0-∞) of more than 3000 h*ng/ml. In someembodiments, the rofecoxib formulation achieves a mean AUC_(0-∞) of morethan 3400 h*ng/ml. In some embodiments, the rofecoxib formulationachieves a mean AUC_(0-∞) of more than 3500 h*ng/ml.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 20 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof, wherein a singleadministration of the formulation to human subjects less than 65 yearsof age achieves a mean Cmax plasma concentration within 80% to 125% of259 ng/ml. In some embodiments, the rofecoxib formulation achieves amean Cmax plasma concentration within 80% to 125% of 259 ng/ml and amean AUC_(0-∞) within 80% to 125% of 3550 h*ng/ml. In some embodiments,the rofecoxib formulation achieves a mean plasma AUC_(0-∞) of about2840-4438 h*ng/ml and a mean plasma Cmax of about 207-324 ng/mlfollowing oral administration of a single dose of the formulation to apopulation of healthy adults less than 65 years of age in a fastedstate. In some embodiments, the population of healthy adults are lessthan 60 years of age.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 20 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof, wherein the formulationreaches a Cmax plasma concentration of least 170 ng/ml in the subject.

In some embodiments, the rofecoxib formulation reaches a Cmax plasmaconcentration level of at least 190 ng/ml. In some embodiments, therofecoxib formulation reaches a Cmax plasma concentration level of atleast 205 ng/ml. In some embodiments, the rofecoxib formulation reachesa Cmax plasma concentration level of at least 220 ng/ml. In someembodiments, the rofecoxib formulation reaches a Cmax plasmaconcentration level of at least 235 ng/ml. In some embodiments, therofecoxib formulation reaches a Cmax plasma concentration level of atleast 250 ng/ml.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a 20 mg solid dosage formulation of rofecoxib or apharmaceutically acceptable salt thereof, wherein the formulationreaches an AUC_(0-∞) of more than 3000 h*ng/ml in the subject.

In some embodiments, the rofecoxib formulation reaches an AUC_(0-∞) ofmore than 3200 h*ng/ml. In some embodiments, the rofecoxib formulationreaches an AUC_(0-∞) of more than 3300 h*ng/ml. In some embodiments, therofecoxib formulation reaches an AUC_(0-∞) of more than 3400 h*ng/ml. Insome embodiments, the rofecoxib formulation reaches an AUC_(0-∞) of morethan 3500 h*ng/ml. In some embodiments, the rofecoxib formulationreaches an AUC_(0-∞) of more than 3525 h*ng/ml. In some embodiments, therofecoxib formulation reaches an AUC_(0-∞) of 3550 h*ng/ml or more. Insome embodiments, the rofecoxib formulation achieves a mean Cmax plasmaconcentration within 80% to 125% of 259 ng/ml and a mean AUC_(0-∞)within 80% to 125% of 3550 h*ng/ml.

In certain aspects, the subject matter disclosed herein provides apharmaceutically acceptable formulation comprising a granular componentand an extragranular component, wherein the granular component comprisesan intragranular component comprising rofecoxib or a pharmaceuticallyacceptable salt thereof and one or more disintegrants, and wherein theextragranular component comprises one or more disintegrants.

In some embodiments, the one or more disintegrants in the granularcomponent is selected from starches, clays, celluloses, algins, gums,cross-linked polymers, and combinations thereof. In some embodiments,the one or more disintegrants in the granular component is selected fromcroscarmellose, crospovidone, sodium starch glycolate, and combinationsthereof. In some embodiments, one or more disintegrants in the granularcomponent is croscarmellose sodium. In some embodiments, the one or moredisintegrants in the granular component is about 1% (w/w) to about 8%(w/w) of the formulation. In some embodiments, the one or moredisintegrants in the granular component is about 1% (w/w) to about 6%(w/w) of the formulation. In some embodiments, the one or moredisintegrants in the granular component is about 1% (w/w) to about 4%(w/w) of the formulation. In some embodiments, the one or moredisintegrants in the extragranular component is selected from starches,clays, celluloses, algins, gums, cross-linked polymers, and combinationsthereof. In some embodiments, the one or more disintegrants in theextragranular component is selected from croscarmellose, crospovidone,sodium starch glycolate, and combinations thereof. In some embodiments,the one or more disintegrants in the extragranular component iscroscarmellose sodium.

In some embodiments, the disintegrant in the extragranular component isabout 1% (w/w) to about 8% (w/w) of the formulation. In someembodiments, the disintegrant in the extragranular component is about 1%(w/w) to about 6% (w/w) of the formulation. In some embodiments, thedisintegrant in the extragranular component is about 1% (w/w) to about4% (w/w) of the formulation. In some embodiments, the disintegrant inthe granular component and the disintegrant in the extragranularcomponent are together about 2% (w/w) to about 12% (w/w) of theformulation. In some embodiments, the disintegrant in the granularcomponent and the disintegrant in the extragranular component aretogether about 2% (w/w) to about 10% (w/w) of the formulation. In someembodiments, the disintegrant in the granular component and thedisintegrant in the extragranular component are together about 2% (w/w)to about 8% (w/w) of the formulation. In some embodiments, the ratio ofgranular disintegrant to extragranular disintegrant is about 40% toabout 60% (w/w). In some embodiments, the ratio of granular disintegrantto extragranular disintegrant is about 45% to about 55% (w/w). In someembodiments, the ratio of granular disintegrant to extragranulardisintegrant is about 50% to about 50% (w/w). In some embodiments, theratio of granular disintegrant to extragranular disintegrant is about55% to about 45% (w/w). In some embodiments, the ratio of granulardisintegrant to extragranular disintegrant is about 60% to about 40%(w/w).

In some embodiments, the pharmaceutically acceptable formulation formfurther comprises one or more of a diluent, a binder, a coloring agent,and a lubricant. In some embodiments, at least a portion of the diluentis in the granular component. In some embodiments, the diluent isselected from dicalcium phosphate, calcium sulfate, lactose, cellulose,kaolin, mannitol, sodium chloride, dry starch, powdered sugar, sorbitol,sucrose, inositol, and combinations thereof. In some embodiments, thediluent is selected from lactose, cellulose, or a combination thereof.In some embodiments, the diluent is selected from lactose monohydrate,microcrystalline cellulose, or a combination thereof.

In some embodiments, the lactose monohydrate is about 35% (w/w) to about45% (w/w) of the formulation. In some embodiments, the lactosemonohydrate is about 37% (w/w) to about 42% (w/w) of the formulation. Insome embodiments, the lactose monohydrate is about 39% (w/w) to about40% (w/w) of the formulation. In some embodiments, the microcrystallinecellulose is about 35% (w/w) to about 45% (w/w) of the formulation. Insome embodiments, the microcrystalline cellulose is about 37% (w/w) toabout 42% (w/w) of the formulation. In some embodiments, themicrocrystalline cellulose is about 39% (w/w) to about 40% (w/w) of theformulation. In some embodiments, the diluent is about 75% (w/w) toabout 85% (w/w) of the formulation. In some embodiments, the diluent isabout 77% (w/w) to about 82% (w/w) of the formulation. In someembodiments, the diluent is about 78% (w/w) to about 80% (w/w) of theformulation.

In some embodiments, at least a portion of the binder is in the granularcomponent. In some embodiments, the binder is selected from starches,gelatins, sugars, gums, waxes, water, alcohols, celluloses, andcombinations thereof. In some embodiments, the binder is selected fromacacia gum, tragacanth, corn starch, methyl cellulose, panwar gum,ghatti gum, mucilage of isapol husks, carboxymethylcellulose,methylcellulose, polyvinylpyrrolidone, sucrose, glucose, dextrose,molasses, lactose, and combinations thereof. In some embodiments, thebinder is hydroxypropyl cellulose.

In some embodiments, the binder is about 1% (w/w) to about 5% (w/w) ofthe formulation. In some embodiments, the binder is about 2% (w/w) toabout 4% (w/w) of the formulation. In some embodiments, the binder isabout 2.5% (w/w) to about 3.5% (w/w) of the formulation.

In some embodiments, at least a portion of the coloring agent is in theextragranular component. In some embodiments, the coloring agent ispigment blend yellow. In some embodiments, the coloring agent is about0.30% (w/w) to about 0.60% (w/w) of the formulation.

In some embodiments, at least a portion of the lubricant is in theextragranular component. In some embodiments, the lubricant is selectedfrom talc, magnesium stearate, calcium stearate, stearic acid, metallicstearate, hydrogenated vegetable oils, and polyethylene glycol, cornstarch, boric acids, sodium chloride, sodium lauryl sulphate. In someembodiments, the lubricant is magnesium stearate. In some embodiments,the lubricant is about 0.10% (w/w) to about 1% (w/w) of the formulation.In some embodiments, the lubricant is about 0.50% (w/w) of theformulation.

In some embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is about 5% (w/w) to about 30% (w/w) of the formulation. In someembodiments, the rofecoxib or pharmaceutically acceptable salt thereofis about 10% (w/w) to about 20% (w/w) of the formulation. In someembodiments, the rofecoxib or pharmaceutically acceptable salt thereofis about 12% (w/w) to about 13% (w/w) of the formulation.

In some embodiments, the formulation comprises about 10 mg of therofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the formulation comprises about 12.5 mg of the rofecoxib orpharmaceutically acceptable salt thereof. In some embodiments, theformulation comprises about 17.5 mg of the rofecoxib or pharmaceuticallyacceptable salt thereof. In some embodiments, the formulation comprisesabout 20 mg of the rofecoxib or pharmaceutically acceptable saltthereof. In some embodiments, the formulation comprises about 25 mg ofthe rofecoxib or pharmaceutically acceptable salt thereof.

In some embodiments, the rofecoxib is substantially pure. In someembodiments, the rofecoxib is highly pure. In some embodiments, thehighly pure rofecoxib comprises less than about 0.1% total impurities.In some embodiments, the highly pure rofecoxib comprises less than about0.075% total impurities. In some embodiments, the highly pure rofecoxibcomprises less than about 0.050% total impurities. In some embodiments,the highly pure rofecoxib comprises less than about 0.025% totalimpurities. In some embodiments, the highly pure rofecoxib comprisesless than about 0.001% total impurities.

In some embodiments, the rofecoxib is substantially pure or highly pure.In some embodiments, the highly pure rofecoxib comprises less than about0.10%, 0.05%, 0.02%, or 0.01% of4-[4-(methylsulphonyl)phenyl]-3-phenyl-2,5-furandione. In someembodiments, the highly pure rofecoxib comprises less than about 0.10%,0.05%, 0.02%, or 0.01% of4-[4-(methylsulfonyl)phenyl]-3-phenyl-5-hydroxyfuran-2-one. In someembodiments, the highly pure rofecoxib comprises less than about 0.10%,0.05%, 0.02%, or 0.01% of4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some embodiments,the highly pure rofecoxib comprises less than about 0.10%, 0.05%, 0.02%,or 0.01% of 4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone.

In some embodiments, the formulation is suitable for oraladministration. In some embodiments, the formulation is a solid dosageform. In some embodiments, the solid dosage form is an oral tablet.

In some embodiments, the oral tablet provides a dissolution rate of atleast about 80% of the rofecoxib or pharmaceutically acceptable saltthereof by about 15 minutes. In some embodiments, the oral tabletprovides a dissolution rate of at least about 85% of the rofecoxib orpharmaceutically acceptable salt thereof by about 15 minutes. In someembodiments, the oral tablet provides a dissolution rate of at leastabout 90% of the rofecoxib or pharmaceutically acceptable salt thereofby about 15 minutes. In some embodiments, the oral tablet provides adissolution rate of at least about 95% of the rofecoxib orpharmaceutically acceptable salt thereof by about 15 minutes. In someembodiments, the oral tablet provides a dissolution rate of at leastabout 100% of the rofecoxib or pharmaceutically acceptable salt thereofby about 15 minutes.

In some embodiments, the dissolution rate is measured in about 1% SDS ata paddle speed of about 50 rpm and at a temperature of about 37.0°C.±0.5° C. In some embodiments, the dissolution rate is measured inabout 1% SDS at a paddle speed of about 75 rpm and at a temperature ofabout 37.0° C.±0.5° C. In some embodiments, the dissolution rate ismeasured in about 1.5% SDS at a paddle speed of about 50 rpm and at atemperature of about 37.0° C.±0.5° C. In some embodiments, thedissolution rate is measured in about 1.5% SDS at a paddle speed ofabout 75 rpm and at a temperature of about 37.0° C.±0.5° C. In someembodiments, the dissolution rate is measured in about 2% SDS at apaddle speed of about 50 rpm and at a temperature of about 37.0° C.±0.5°C. In some embodiments, the dissolution rate is measured in about 2% SDSat a paddle speed of about 75 rpm and at a temperature of about 37.0°C.±0.5° C. In some embodiments, the dissolution rate is measured using aUSP Type II apparatus. In some embodiments, the dissolution rate ismeasured with a USP Type II apparatus using 900 mL of 2% SDS, a paddlespeed of 50 rpm, and a temperature of 37.0° C.±0.5°.

In some embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 35% of thegranules are less than about 75 μm. In some embodiments, the rofecoxibor pharmaceutically acceptable salt thereof is formulated into granulesand at least about 55% of the granules are less than about 150 μm. Insome embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 75% of thegranules are less than about 250 μm. In some embodiments, the rofecoxibor pharmaceutically acceptable salt thereof is formulated into granulesand at least about 85% of the granules are less than about 425 μm. Insome embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 90% of thegranules are less than about 1000 μm.

In some embodiments, the formulation is a solid dosage formulationcomprising 12.5 mg, 17.5 mg, 20 mg, or 25 mg of rofecoxib, and whereinthe formulation reaches a median time to Cmax plasma concentration in 3hours or less following a single administration of the formulation tohuman subjects less than 65 years of age.

In some embodiments, the formulation reaches a mean Cmax plasmaconcentration in less than 3 hours following administration. In someembodiments, the formulation reaches a mean Cmax plasma concentration inless than 2.5 hours following administration. In some embodiments, theformulation reaches a mean Cmax plasma concentration in less than 2hours following administration. In some embodiments, the formulation isa solid dosage formulation comprising 25 mg of rofecoxib, and wherein asingle administration of the formulation to human subjects less than 65years of age achieves a mean Cmax plasma concentration of more than 240ng/ml. In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 300 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 320ng/ml. In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 350 ng/ml.

In some embodiments, the formulation is a solid dosage formulationcomprising 25 mg of rofecoxib, and wherein a single administration ofthe formulation to human subjects less than 65 years of age achieves amean AUC_(0-∞) of more than 4500 h*ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 4700 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 5000h*ng/ml.

In some embodiments, the formulation is a solid dosage formulationcomprising 25 mg of rofecoxib, and wherein a single administration ofthe formulation in human subjects less than 65 years of age reaches amean Cmax plasma concentration of more than 240 ng/ml in less than 3hours following administration with a mean AUC_(0-∞) of more than 4250h*ng/ml.

In certain aspects, the subject matter disclosed herein provides a soliddosage formulation comprising 10 mg to 50 mg of rofecoxib and apharmaceutically acceptable carrier, wherein a single administration ofthe formulation in human subjects less than 65 years of age achieves amean Cmax plasma concentration from 9.8 ng/ml to 16 ng/ml for each 1 mgof rofecoxib in the formulation.

In some embodiments, the formulation achieves a mean Cmax plasmaconcentration from 10 ng/ml to 14 ng/ml for each 1 mg of rofecoxib inthe formulation. In some embodiments, the formulation achieves a meanCmax plasma concentration from 10 ng/ml to 13 ng/ml for each 1 mg ofrofecoxib in the formulation. In some embodiments, the formulationachieves a mean Cmax plasma concentration from 80% to 125% of 12.8ng/ml.

In certain aspects, the subject matter disclosed herein provides a soliddosage formulation comprising 10 mg to 50 mg of rofecoxib and apharmaceutically acceptable carrier, wherein a single administration ofthe formulation in human subjects less than 65 years of age achieves amean AUC_(0-∞) of 170 h*ng/ml to 235 h*ng/ml for each 1 mg of rofecoxibin the formulation.

In some embodiments, the formulation achieves a mean AUC_(0-∞) of 170h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib in the formulation. Insome embodiments, the formulation achieves a mean AUC_(0-∞) of 177h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib in the formulation. Insome embodiments, the formulation achieves a mean AUC_(0-∞) of 180h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib in the formulation. Insome embodiments, the formulation achieves a mean AUC_(0-∞) of 190h*ng/ml to 215 h*ng/ml for each 1 mg of rofecoxib in the formulation.

In certain aspects, the subject matter disclosed herein provides amethod of inhibiting COX-2 in a subject by administering theformulations described herein.

In certain aspects, the subject matter disclosed herein provides amethod of inhibiting COX-2 in a subject by administering a solid dosageformulation comprising 17.5 mg of rofecoxib.

In some embodiments, the formulation is a solid dosage formulationcomprising 17.5 mg of rofecoxib, wherein a single administration of theformulation to human subjects less than 65 years of age achieves a meanCmax that is equal to or greater than that reported by Schwartz, J. I.,et al. Clin. Drug Invent. 2003, 23 (8): 503-509 for a rofecoxib 25 mgtablet. In some embodiments, the formulation is a solid dosageformulation comprising 17.5 mg of rofecoxib, wherein a singleadministration of the formulation to human subjects less than 65 yearsof age achieves a mean Cmax that is equal to or greater than thatreported in the FDA-approved label for VIOXX for a single 25-mg dose ofVIOXX. In some embodiments, the formulation is a solid dosageformulation comprising 17.5 mg of rofecoxib, wherein the formulationachieves equal or greater efficacy in the treatment of pain, fever, orinflammation in a subject than a 25 mg tablet of VIOXX (as approvedunder U.S. New Drug Applications 021042 and 021647). In someembodiments, the formulation is a solid dosage formulation comprising 20mg of rofecoxib, where a single administration of the formulation tohuman subjects less than 65 years of age achieves a mean AUC_(0-∞) thatis equal to or greater than that reported by Schwartz, J. I., et al.Clin. Drug Invent. 2003, 23 (8): 503-509 for a rofecoxib 25 mg tablet.In some embodiments, the formulation is a solid dosage formulationcomprising 20 mg of rofecoxib, where a single administration of theformulation to human subjects less than 65 years of age achieves a meanCmax that is equal to or greater than that reported by Schwartz, J. I.,et al. Clin. Drug Invent. 2003, 23 (8): 503-509 for a rofecoxib 25 mgtablet. In some embodiments, the formulation is a solid dosageformulation comprising 20 mg of rofecoxib, wherein a singleadministration of the formulation to human subjects less than 65 yearsof age achieves a mean AUC_(0-∞) that is equal to or greater than thatreported in the FDA-approved label for VIOXX for a single 25-mg dose ofVIOXX. In some embodiments, the formulation is a solid dosageformulation comprising 20 mg of rofecoxib, wherein a singleadministration of the formulation to human subjects less than 65 yearsof age achieves a mean Cmax that is equal to or greater than thatreported in the FDA-approved label for VIOXX for a single 25-mg dose ofVIOXX. In some embodiments, the formulation is a solid dosageformulation comprising 20 mg of rofecoxib, wherein the formulationachieves equal or greater efficacy in the treatment of pain, fever, orinflammation in a subject than a 25 mg tablet of VIOXX (as approvedunder U.S. New Drug Applications 021042 and 021647).

In some embodiments, the patient is age 2 or older.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a patient byadministering the formulations as described herein.

In some embodiments, the human subjects are healthy human subjects. Insome embodiments, the patient is age 2 or older.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a patient populationcomprising providing a solid dosage formulation comprising 10 mg to 50mg of rofecoxib to the patient population for inhibiting COX-2, whereinthe formulation achieves a mean Cmax plasma concentration of between 80to 125% of 12.8 ng/ml for each 1 mg of rofecoxib in the formulationfollowing single administration of the formulation in the patientpopulation.

Further Embodiments of the Present Subject Matter

In certain aspects, the subject matter disclosed herein provides apharmaceutically acceptable formulation comprising granules. In someembodiments, the pharmaceutically acceptable formulation comprises agranular component and an extragranular component, wherein the granularcomponent comprises an intragranular component comprising rofecoxib or apharmaceutically acceptable salt thereof and one or more disintegrants,and wherein the extragranular component comprises one or moredisintegrants.

In some embodiments, the one or more disintegrants in the granularcomponent is selected from starches, clays, celluloses, algins, gums,cross-linked polymers, and combinations thereof. In some embodiments,the one or more disintegrants in the granular component is selected fromcroscarmellose, crospovidone, sodium starch glycolate, and combinationsthereof.

In some embodiments, the one or more disintegrants in the granularcomponent is croscarmellose sodium. In some embodiments, the one or moredisintegrants in the granular component is about 1% (w/w) to about 8%(w/w) of the formulation. In some embodiments, the one or moredisintegrants in the granular component is about 1% (w/w) to about 6%(w/w) of the formulation. In some embodiments, the one or moredisintegrants in the granular component is about 1% (w/w) to about 4%(w/w) of the formulation.

In some embodiments, the one or more disintegrants in the extragranularcomponent is selected from starches, clays, celluloses, algins, gums,cross-linked polymers, and combinations thereof. In some embodiments,the one or more disintegrants in the extragranular component is selectedfrom croscarmellose, crospovidone, sodium starch glycolate, andcombinations thereof. In some embodiments, the one or more disintegrantsin the extragranular component is croscarmellose sodium. In someembodiments, the disintegrant in the extragranular component is about 1%(w/w) to about 8% (w/w) of the formulation. In some embodiments, thedisintegrant in the extragranular component is about 1% (w/w) to about6% (w/w) of the formulation. In some embodiments, the disintegrant inthe extragranular component is about 1% (w/w) to about 4% (w/w) of theformulation.

In some embodiments, the disintegrant in the granular component and thedisintegrant in the extragranular component are together about 2% (w/w)to about 12% (w/w) of the formulation. In some embodiments, thedisintegrant in the granular component and the disintegrant in theextragranular component are together about 2% (w/w) to about 10% (w/w)of the formulation. In some embodiments, the disintegrant in thegranular component and the disintegrant in the extragranular componentare together about 2% (w/w) to about 8% (w/w) of the formulation.

In some embodiments, the ratio of granular disintegrant to extragranulardisintegrant is about 40% (w/w) to about 60% (w/w). In some embodiments,the ratio of granular disintegrant to extragranular disintegrant isabout 45% (w/w) to about 55% (w/w). In some embodiments, the ratio ofgranular disintegrant to extragranular disintegrant is about 50% (w/w)to about 50% (w/w). In some embodiments the ratio of granulardisintegrant to extragranular disintegrant is about 55% (w/w) to about45% (w/w). In some embodiments the ratio of granular disintegrant toextragranular disintegrant is about 60% (w/w) to about 40% (w/w).

In some embodiments, the pharmaceutically acceptable formulation furthercomprising one or more of a diluent, a binder, a coloring agent, and alubricant. In some embodiments, at least a portion of the diluent is inthe granular component. In some embodiments, the diluent is selectedfrom dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin,mannitol, sodium chloride, dry starch, powdered sugar, sorbitol,sucrose, inositol, and combinations thereof. In some embodiments, thediluent is selected from lactose, cellulose, or a combination thereof.In some embodiments, the diluent is selected from lactose monohydrate,microcrystalline cellulose, or a combination thereof.

In some embodiments, the lactose monohydrate is about 35% (w/w) to about45% (w/w) of the formulation. In some embodiments, the lactosemonohydrate is about 37% (w/w) to about 42% (w/w) of the formulation. Insome embodiments, the lactose monohydrate is about 39% (w/w) to about40% (w/w) of the formulation.

In some embodiments, the microcrystalline cellulose is about 35% (w/w)to about 45% (w/w) of the formulation. In some embodiments, themicrocrystalline cellulose is about 37% (w/w) to about 42% (w/w) of theformulation. In some embodiments, the microcrystalline cellulose isabout 39% (w/w) to about 40% (w/w) of the formulation.

In some embodiments, the diluent is about 75% (w/w) to about 85% (w/w)of the formulation. In some embodiments, diluent is about 77% (w/w) toabout 82% (w/w) of the formulation. In some embodiments, the diluent isabout 78% (w/w) to about 80% (w/w) of the formulation.

In some embodiments, at least a portion of the binder is in the granularcomponent. In some embodiments, the binder is selected from starches,gelatins, sugars, gums, waxes, water, alcohols, celluloses, andcombinations thereof. In some embodiments, the binder is selected fromacacia gum, tragacanth, corn starch, methyl cellulose, panwar gum,ghatti gum, mucilage of isapol husks, carboxymethylcellulose,methylcellulose, polyvinylpyrrolidone, sucrose, glucose, dextrose,molasses, lactose, and combinations thereof. In some embodiments, thebinder is hydroxypropyl cellulose. In some embodiments, the binder isabout 1% (w/w) to about 5% (w/w) of the formulation. In someembodiments, binder is about 2% (w/w) to about 4% (w/w) of theformulation. In some embodiments, the binder is about 2.5% (w/w) toabout 3.5% (w/w) of the formulation.

In some embodiments, at least a portion of the coloring agent is in theextragranular component. In some embodiments, the coloring agent ispigment blend yellow. In some embodiments, the coloring agent is about0.30% (w/w) to about 0.60% (w/w) of the formulation.

In some embodiments, at least a portion of the lubricant is in theextragranular component. In some embodiments, the lubricant is selectedfrom talc, magnesium stearate, calcium stearate, stearic acid, metallicstearate, hydrogenated vegetable oils, and polyethylene glycol, cornstarch, boric acids, sodium chloride, sodium lauryl sulphate. In someembodiments, the lubricant is magnesium stearate. In some embodiments,the lubricant is about 0.10% (w/w) to about 1% (w/w) of the formulation.In some embodiments, the lubricant is about 0.50% (w/w) of theformulation.

In some embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is about 5% (w/w) to about 30% (w/w) of the formulation. In someembodiments, the rofecoxib or pharmaceutically acceptable salt thereofis about 10% (w/w) to about 20% (w/w) of the formulation. In someembodiments, the rofecoxib or pharmaceutically acceptable salt thereofis about 12% (w/w) to about 13% (w/w) of the formulation. In someembodiments, the formulation comprises about 10 mg of the rofecoxib orpharmaceutically acceptable salt thereof. In some embodiments, theformulation comprises about 10.5 mg of the rofecoxib or pharmaceuticallyacceptable salt thereof. In some embodiments, the formulation comprisesabout 11 mg of the rofecoxib or pharmaceutically acceptable saltthereof. In some embodiments, the formulation comprises about 11.5 mg ofthe rofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the formulation comprises about 12 mg of the rofecoxib orpharmaceutically acceptable salt thereof. In some embodiments, theformulation comprises about 12.5 mg of the rofecoxib or pharmaceuticallyacceptable salt thereof. In some embodiments, the formulation comprisesabout 17.5 mg of the rofecoxib or pharmaceutically acceptable saltthereof. In some embodiments, the formulation comprises about 20 mg ofthe rofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the formulation comprises about 21 mg of the rofecoxib orpharmaceutically acceptable salt thereof. In some embodiments, theformulation comprises about 22 mg of the rofecoxib or pharmaceuticallyacceptable salt thereof. In some embodiments, the formulation comprisesabout 22.5 mg of the rofecoxib or pharmaceutically acceptable saltthereof. In some embodiments, the formulation comprises about 25 mg ofthe rofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the formulation comprises about 50 mg of the rofecoxib orpharmaceutically acceptable salt thereof.

In some embodiments, the rofecoxib is highly pure. In some embodiments,the highly pure rofecoxib comprises less than about 0.1% totalimpurities. In some embodiments, the highly pure rofecoxib comprisesless than about 0.075% total impurities. In some embodiments, the highlypure rofecoxib comprises less than about 0.050% total impurities. Insome embodiments, the highly pure rofecoxib comprises less than about0.025% total impurities. In some embodiments, the highly pure rofecoxibcomprises less than about 0.001% total impurities.

In some embodiments, the highly pure rofecoxib comprises less than about0.10%, 0.05%, 0.02%, or 0.01% of4-[4-(methylsulphonyl)phenyl]-3-phenyl-2,5-furandione. In someembodiments, the highly pure rofecoxib comprises less than about 0.10%,0.05%, 0.02%, or 0.01% of4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some embodiments,the highly pure rofecoxib comprises less than about 0.10%, 0.05%, 0.02%,or 0.01% of 4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In someembodiments, the highly pure rofecoxib comprises less than about 0.10%,0.05%, 0.02%, or 0.01% of4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone.

In some embodiments, the formulation is suitable for oraladministration. In some embodiments, the formulation is a solid dosageform. In some embodiments, the solid dosage form is an oral tablet. Insome embodiments, the oral tablet provides a dissolution rate of atleast about 80% of the rofecoxib or pharmaceutically acceptable saltthereof by about 15 minutes. In some embodiments, the oral tabletprovides a dissolution rate of at least about 85% of the rofecoxib orpharmaceutically acceptable salt thereof by about 15 minutes. In someembodiments, the oral tablet provides a dissolution rate of at leastabout 90% of the rofecoxib or pharmaceutically acceptable salt thereofby about 15 minutes. In some embodiments, the oral tablet provides adissolution rate of at least about 95% of the rofecoxib orpharmaceutically acceptable salt thereof by about 15 minutes. In someembodiments, the oral tablet provides a dissolution rate of at leastabout 100% of the rofecoxib or pharmaceutically acceptable salt thereofby about 15 minutes.

In some embodiments, the dissolution rate is measured in about 1% SDS ata paddle speed of about 50 rpm and at a temperature of about 37.0°C.±0.5° C. In some embodiments, the dissolution rate is measured inabout 1% SDS at a paddle speed of about 75 rpm and at a temperature ofabout 37.0° C.±0.5° C. In some embodiments, the dissolution rate ismeasured in about 1.5% SDS at a paddle speed of about 50 rpm and at atemperature of about 37.0° C.±0.5° C. In some embodiments, thedissolution rate is measured in about 1.5% SDS at a paddle speed ofabout 75 rpm and at a temperature of about 37.0° C.±0.5° C. In someembodiments, the dissolution rate is measured in about 2% SDS at apaddle speed of about 50 rpm and at a temperature of about 37.0° C.±0.5°C. In some embodiments, the dissolution rate is measured in about 2% SDSat a paddle speed of about 75 rpm and at a temperature of about 37.0°C.±0.5° C. In some embodiments, the dissolution rate is measured using aUSP Type II apparatus. In some embodiments, the dissolution rate ismeasured with a USP Type II apparatus using 900 mL of 2% SDS, a paddlespeed of 50 rpm, and a temperature of 37.0° C.±0.5°.

In some embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 35% of thegranules are less than about 75 μm. In some embodiments, the rofecoxibor pharmaceutically acceptable salt thereof is formulated into granulesand at least about 55% of the granules are less than about 150 μm. Insome embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 75% of thegranules are less than about 250 μm. In some embodiments, the rofecoxibor pharmaceutically acceptable salt thereof is formulated into granulesand at least about 85% of the granules are less than about 425 μm. Insome embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 90% of thegranules are less than about 1000 μm.

In some embodiments, a 17.5 mg solid dosage formulation of rofecoxibreaches a median time to Cmax plasma concentration in 4 hours or lessfollowing single administration of the formulation to human subjects. Insome embodiments, a 17.5 mg solid dosage formulation of rofecoxibreaches a median time to Cmax plasma concentration in 3 hours or lessfollowing administration. In some embodiments, a 17.5 mg solid dosageformulation of rofecoxib reaches a mean Cmax plasma concentration 2.5hours following administration. In some embodiments, a 17.5 mg soliddosage formulation of rofecoxib reaches a median time to Cmax plasmaconcentration in 2 hours or less following administration. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 100 ng/ml. In some embodiments, a17.5 mg solid dosage formulation of rofecoxib has a mean Cmax plasmaconcentration of more than 150 ng/ml, 167 ng/ml, or 190 ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 200 ng/ml. In some embodiments, a17.5 mg solid dosage formulation of rofecoxib has a mean Cmax plasmaconcentration of more than 220 ng/ml. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib has a mean Cmax plasmaconcentration of more than 250 ng/ml. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib has a mean Cmax plasmaconcentration of more than 280 ng/ml. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib has a mean AUC_(0-∞) of more than1750 h*ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean AUC_(0-∞) of more than 2000 h*ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 2500 h*ng/ml. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib has a mean AUC_(0-∞) of more than3000 h*ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean AUC_(0-∞) of more than 3100 h*ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 3500 h*ng/ml. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib has a mean AUC_(0-∞) of more than4000 h*ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean AUC_(0-∞) of more than 4500 h*ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib reaches aCmax plasma concentration of least 167 ng/ml, 170 ng/ml, 175 ng/ml, 180ng/ml, or higher following single administration of the formulation to ahuman subject. In some embodiments, a 17.5 mg solid dosage formulationof rofecoxib reaches an AUC_(0-∞) of at least 2600 h*ng/ml, 2750h*ng/ml, 2900 h*ng/ml, 3050 h*ng/ml, 3100 h*ng/ml, 3200 h*ng/ml, 3350h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml or higher following singleadministration of the formulation to a human subject.

In some embodiments, a 20 mg solid dosage formulation of rofecoxibreaches a median time to Cmax plasma concentration in 4 hours or lessfollowing single administration of the formulation to human subjects. Insome embodiments, a 20 mg solid dosage formulation of rofecoxib reachesa median time to Cmax plasma concentration in 3 hours or less followingadministration. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib reaches a median time to Cmax plasma concentration in 2.5hours or less following administration. In some embodiments, a 20 mgsolid dosage formulation of rofecoxib reaches a median time to Cmaxplasma concentration in 2 hours or less following administration. Insome embodiments, a 20 mg solid dosage formulation of rofecoxib has amean Cmax plasma concentration of more than 150 ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 191 ng/ml, 200 ng/ml, 215 ng/ml,or 225 ng/ml. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib has a mean Cmax plasma concentration of more than 250 ng/ml.In some embodiments, a 20 mg solid dosage formulation of rofecoxib has amean Cmax plasma concentration of more than 258 ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 300 ng/ml. In some embodiments, a20 mg solid dosage formulation of rofecoxib has a mean AUC_(0-∞) of morethan 2000 h*ng/ml. In some embodiments, a 20 mg solid dosage formulationof rofecoxib has a mean AUC_(0-∞) of more than 2500 h*ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 3000 h*ng/ml. In some embodiments, a 20 mg soliddosage formulation of rofecoxib has a mean AUC_(0-∞) of more than 3400h*ng/ml. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib has a mean AUC_(0-∞) of more than 3500 h*ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 4000 h*ng/ml. In some embodiments, a 20 mg soliddosage formulation of rofecoxib reaches a Cmax plasma concentration ofleast 190 ng/ml, 205 ng/ml, 220 ng/ml, 235 ng/ml, 250 ng/ml, or higherfollowing single administration of the formulation to a human subject.In some embodiments, a 20 mg solid dosage formulation of rofecoxibreaches an AUC_(0-∞) of at least 3000 h*ng/ml, 3200 h*ng/ml, 3350h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800 h*ng/ml, 3950 h*ng/ml, orhigher following single administration of the formulation to a humansubject. In some embodiments, the rofecoxib formulation achieves a meanCmax plasma concentration within 80% to 125% of 259 ng/ml and a meanAUC_(0-∞) within 80% to 125% of 3550 h*ng/ml. In some embodiments, therofecoxib formulation achieves a mean plasma AUC_(0-∞) of about2840-4438 h*ng/ml and a mean plasma Cmax of about 207-324 ng/mlfollowing oral administration of a single dose of the formulation to apopulation of healthy adults less than 65 years of age in a fastedstate. In some embodiments, the population of healthy adults are lessthan 60 years of age.

In some embodiments, a 25 mg solid dosage formulation of rofecoxibreaches a mean Cmax plasma concentration in less than 3 hours followingsingle administration of the formulation to human subjects. In someembodiments, a 25 mg solid dosage formulation of rofecoxib reaches amean Cmax plasma concentration in less than 2.5 hours followingadministration. In some embodiments, a 25 mg solid dosage formulation ofrofecoxib reaches a mean Cmax plasma concentration in less than 2 hoursfollowing administration. In some embodiments, a 25 mg solid dosageformulation of rofecoxib has a mean Cmax plasma concentration of morethan 240 ng/ml. In some embodiments, a 25 mg solid dosage formulation ofrofecoxib has a mean Cmax plasma concentration of more than 300 ng/ml.In some embodiments, a 25 mg solid dosage formulation of rofecoxib has amean Cmax plasma concentration of more than 320 ng/ml. In someembodiments, a 25 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 350 ng/ml. In some embodiments, a25 mg solid dosage formulation of rofecoxib has a mean AUC_(0-∞) of morethan 4250 h*ng/ml. In some embodiments, a 25 mg solid dosage formulationof rofecoxib has a mean AUC_(0-∞) of more than 4500 h*ng/ml. In someembodiments, a 25 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 4550 h*ng/ml. In some embodiments, a 25 mg soliddosage formulation of rofecoxib has a mean AUC_(0-∞) of more than 4700h*ng/ml. In some embodiments, a 25 mg solid dosage formulation ofrofecoxib reaches a mean Cmax plasma concentration of more than 240ng/ml in median time of about 3 hours or less following administrationwith an AUC_(0-∞) of more than 4250 h*ng/ml.

In some embodiments, a solid dosage formulation of 10 mg to 50 mg ofrofecoxib achieves a mean Cmax plasma concentration from 9.8 ng/ml to 16ng/ml for each 1 mg of rofecoxib in the formulation following singleadministration of the formulation to human subjects. In someembodiments, the solid dosage formulation of rofecoxib achieves a meanCmax plasma concentration from 10 ng/ml to 14 ng/ml for each 1 mg ofrofecoxib in the formulation. In some embodiments, the solid dosageformulation of rofecoxib achieves a mean Cmax plasma concentration from10 ng/ml to 13 ng/ml for each 1 mg of rofecoxib in the formulation. Insome embodiments, the solid dosage formulation of rofecoxib achieves amean Cmax plasma concentration from 80% to 125% of 12.8 ng/ml. In someembodiments, the solid dosage formulation of rofecoxib reaches a meanAUC_(0-∞) of 170 h*ng/ml to 235 h*ng/ml for each 1 mg of rofecoxib inthe formulation. In some embodiments, the solid dosage formulation ofrofecoxib reaches a mean AUC_(0-∞) of 170 h*ng/ml to 225 h*ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, theformulation achieves a mean AUC_(0-∞) of 177 h*ng/ml to 225 h*ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, theformulation achieves a mean AUC_(0-∞) of 180 h*ng/ml to 225 h*ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, thesolid dosage formulation of rofecoxib reaches a mean AUC_(0-∞) of 190h*ng/ml to 215 h*ng/ml for each 1 mg of rofecoxib in the formulation.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a solid dosage formulation comprising 17.5 mg of rofecoxibor a pharmaceutically acceptable salt thereof. In some embodiments, theformulation achieves a median time to Cmax plasma concentration in 4hours or less following single administration of the formulation tohuman subjects. In some embodiments, the formulation achieves a mediantime to Cmax plasma concentration in 3 hours or less followingadministration. In some embodiments, the formulation achieves a mediantime to Cmax plasma concentration in 2.5 hours or less followingadministration. In some embodiments, the formulation achieves a mediantime to Cmax plasma concentration in 2 hours or less followingadministration. In some embodiments, the formulation achieves a meanCmax plasma concentration of more than 100 ng/ml. In some embodiments,the formulation achieves a mean Cmax plasma concentration of more than150 ng/ml, 167 ng/ml, or 190 ng/ml. In some embodiments, the formulationachieves a mean Cmax plasma concentration of more than 200 ng/ml. Insome embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 220 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 250ng/ml. In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 280 ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 1750 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 2000h*ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞)of more than 2500 h*ng/ml. In some embodiments, the formulation achievesa mean AUC_(0-∞) of more than 3000 h*ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 3100 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 3500h*ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞)of more than 4000 h*ng/ml. In some embodiments, the formulation achievesa mean AUC_(0-∞) of more than 4500 h*ng/ml. In some embodiments, theformulation reaches a Cmax plasma concentration of least 167 ng/ml, 170ng/ml, 175 ng/ml, 180 ng/ml, or higher following single administrationof the formulation to a human subject. In some embodiments, theformulation reaches an AUC_(0-∞) of at least 2600 h*ng/ml, 2750 h*ng/ml,2900 h*ng/ml, 3050 h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml,3650 h*ng/ml or higher following single administration of theformulation to a human subject.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a solid dosage formulation comprising 20 mg of rofecoxibor a pharmaceutically acceptable salt thereof. In some embodiments, theformulation achieves a median time to Cmax plasma concentration in 4hours or less following single administration of the formulation tohuman subjects. In some embodiments, the formulation achieves a mediantime to Cmax plasma concentration in 3 hours or less followingadministration. In some embodiments, the formulation achieves a mediantime to Cmax plasma concentration in 2.5 hours or less followingadministration. In some embodiments, the formulation achieves a mediantime to Cmax plasma concentration in 2 hours or less followingadministration. In some embodiments, the formulation achieves a meanCmax plasma concentration of more than 150 ng/ml. In some embodiments,the formulation achieves a mean Cmax plasma concentration of more than191 ng/ml, 200 ng/ml, 215 ng/ml, or 225 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 250ng/ml. In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 258 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 300ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞) ofmore than 2000 h*ng/ml. In some embodiments, the formulation achieves amean AUC_(0-∞) of more than 2500 h*ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 3000 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 3400h*ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞)of more than 3500 h*ng/ml. In some embodiments, the formulation achievesa mean AUC_(0-∞) of more than 4000 h*ng/ml. In some embodiments, theformulation reaches a Cmax plasma concentration of least 190 ng/ml, 205ng/ml, 220 ng/ml, 235 ng/ml, 250 ng/ml, or higher following singleadministration of the formulation to a human subject. In someembodiments, the formulation reaches an AUC_(0-∞) of at least 3000h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800h*ng/ml, 3950 h*ng/ml, or higher following single administration of theformulation to a human subject. In some embodiments, the rofecoxibformulation achieves a mean Cmax plasma concentration within 80% to 125%of 259 ng/ml and a mean AUC_(0-∞) within 80% to 125% of 3550 h*ng/ml. Insome embodiments, the rofecoxib formulation achieves a mean plasmaAUC_(0-∞) of about 2840-4438 h*ng/ml and a mean plasma Cmax of about207-324 ng/ml following oral administration of a single dose of theformulation to a population of healthy adults less than 65 years of agein a fasted state. In some embodiments, the population of healthy adultsare less than 60 years of age.

In certain aspects, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a solid dosage formulation comprising 25 mg of rofecoxibor a pharmaceutically acceptable salt thereof. In some embodiments, theformulation achieves a mean Cmax plasma concentration in less than 3hours following single administration of the formulation to humansubjects. In some embodiments, the formulation achieves a mean Cmaxplasma concentration in less than 2.5 hours following administration. Insome embodiments, the formulation achieves a mean Cmax plasmaconcentration in less than 2 hours following administration. In someembodiments, the formulation achieves a mean Cmax plasma concentrationof more than 240 ng/ml. In some embodiments, the formulation achieves amean Cmax plasma concentration of more than 250 ng/ml. In someembodiments, the formulation achieves a mean Cmax plasma concentrationof more than 300 ng/ml. In some embodiments, the formulation achieves amean Cmax plasma concentration of more than 320 ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 4250h*ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞)of more than 4500 h*ng/ml. In some embodiments, the formulation achievesa mean AUC_(0-∞) of more than 4550 h*ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 4700 h*ng/ml. In someembodiments, the formulation achieves a mean Cmax plasma concentrationof more than 240 ng/ml in less than 3 hours following administrationwith a mean AUC_(0-∞) of more than 4250 h*ng/ml.

In some embodiments, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a solid dosage formulation of 10 mg to 50 mg of rofecoxibthat achieves a mean Cmax plasma concentration from 9.8 ng/ml to 16ng/ml for each 1 mg of rofecoxib in the formulation following singleadministration of the formulation to human subjects. In someembodiments, the solid dosage formulation of rofecoxib achieves a meanCmax plasma concentration from 10 ng/ml to 14 ng/ml for each 1 mg ofrofecoxib in the formulation. In some embodiments, the solid dosageformulation of rofecoxib achieves a mean Cmax plasma concentration from10 ng/ml to 13 ng/ml for each 1 mg of rofecoxib in the formulation. Insome embodiments, the solid dosage formulation of rofecoxib achieves amean Cmax plasma concentration from 80% to 125% of 12.8 ng/ml. In someembodiments, the solid dosage formulation of rofecoxib reaches a meanAUC_(0-∞) of 170 h*ng/ml to 235 h*ng/ml for each 1 mg of rofecoxib inthe formulation. In some embodiments, the solid dosage formulation ofrofecoxib reaches a mean AUC_(0-∞) of 170 h*ng/ml to 225 h*ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, theformulation achieves a mean AUC_(0-∞) of 177 h*ng/ml to 225 h*ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, theformulation achieves a mean AUC_(0-∞) of 180 h*ng/ml to 225 h*ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, thesolid dosage formulation of rofecoxib reaches a mean AUC_(0-∞) of 190h*ng/ml to 215 h*ng/ml for each 1 mg of rofecoxib in the formulation.

In some embodiments, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a solid dosage formulation of 10 mg to 50 mg of rofecoxib,wherein a single administration of the formulation in human femalesubjects less than 65 years of age achieves a mean Cmax plasmaconcentration that is at least 10% greater than that achieved followinga single administration of the formulation to human male subjects lessthan 65 years of age. In some embodiments, the formulation achieves amean Cmax plasma concentration in human female subjects that is at least20% greater than that achieved in human male subjects. In someembodiments, the formulation achieves a mean Cmax plasma concentrationin human female subjects that is at least 25% greater than that achievedin human male subjects. In some embodiments, the formulation comprises17.5 mg to 25 mg of rofecoxib. In some embodiments, the formulationcomprises 17.5 mg of rofecoxib. In some embodiments, the formulationcomprises 20 mg of rofecoxib. In some embodiments, the formulationcomprises 25 mg of rofecoxib. In some embodiments, the human femaleand/or male subjects meet the eligibility criteria of the PK-101 and/orPK-102 studies set forth in Examples 4 and 6.

In some embodiments, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a solid dosage formulation of 10 mg to 50 mg of rofecoxib,wherein a single administration of the formulation in Caucasian subjectsless than 65 years of age achieves a mean AUC_(0-∞) that is greater thanthat achieved following a single administration of the formulation toAfrican American subjects less than 65 years of age. In someembodiments, the formulation achieves a mean AUC_(0-∞) in Caucasiansubjects that is at least 1%, 2%, 5%, 9%, or 10% greater than thatachieved following a single administration of the formulation to AfricanAmerican subjects less than 65 years of age. In some embodiments, theformulation comprises 17.5 mg to 25 mg of rofecoxib. In someembodiments, the formulation comprises 17.5 mg of rofecoxib. In someembodiments, the formulation comprises 20 mg of rofecoxib. In someembodiments, the formulation comprises 25 mg of rofecoxib. In someembodiments, the Caucasian and/or African American subjects meet theeligibility criteria of the PK-101 and/or PK-102 studies set forth inExamples 4 and 6.

In some embodiments, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a solid dosage formulation comprising 12.5 mg ofrofecoxib, wherein the formulation achieves a mean plasma concentrationof at least about 0.2 ng/ml, 0.3 ng/ml, 0.4 ng/ml, or 0.5 ng/ml at 15minutes following single administration of the formulation to humansubjects less than 65 years of age. In some embodiments, the subjectmatter disclosed herein provides a method for treating pain, fever, orinflammation in a subject by administering a solid dosage formulationcomprising 12.5 mg of rofecoxib, wherein the formulation achieves anarithmetic mean plasma concentration of at least about 0.8 ng/ml, 0.9ng/ml, or 1.0 ng/ml at 15 minutes following single administration of theformulation to human subjects less than 65 years of age. In someembodiments, the subject matter disclosed herein provides a method fortreating pain, fever, or inflammation in a subject by administering asolid dosage formulation comprising 17.5 mg of rofecoxib, wherein theformulation achieves a mean plasma concentration of at least about 0.3ng/ml, 0.4 ng/ml, 0.5 ng/ml, or 0.6 ng/ml at 15 minutes following singleadministration of the formulation to human subjects less than 65 yearsof age. In some embodiments, the subject matter disclosed hereinprovides a method for treating pain, fever, or inflammation in a subjectby administering a solid dosage formulation comprising 17.5 mg ofrofecoxib, wherein the formulation achieves an arithmetic mean plasmaconcentration of at least about 1.8 ng/ml, 2.0 ng/ml, 2.2 ng/ml, or 2.4ng/ml at 15 minutes following single administration of the formulationto human subjects less than 65 years of age. In some embodiments, thesubject matter disclosed herein provides a method for treating pain,fever, or inflammation in a subject by administering a solid dosageformulation comprising 20 mg of rofecoxib, wherein the formulationachieves a mean plasma concentration of at least about 0.8 ng/ml, 0.9ng/ml, 1.0 ng/ml, 1.1 ng/ml, or 1.16 ng/ml at 15 minutes followingsingle administration of the formulation to human subjects less than 65years of age. In some embodiments, the subject matter disclosed hereinprovides a method for treating pain, fever, or inflammation in a subjectby administering a solid dosage formulation comprising 20 mg ofrofecoxib, wherein the formulation achieves an arithmetic mean plasmaconcentration of at least about 4.6 ng/ml, 5.0 ng/ml, 5.4 ng/ml, or 5.7ng/ml at 15 minutes following single administration of the formulationto human subjects less than 65 years of age. In some embodiments, thesubject matter disclosed herein provides a method for treating pain,fever, or inflammation in a subject by administering a solid dosageformulation comprising 25 mg of rofecoxib, wherein the formulationachieves a mean plasma concentration of at least about 1.0 ng/ml, 1.1ng/ml, 1.2 ng/ml, or 1.3 ng/ml at 15 minutes following singleadministration of the formulation to human subjects less than 65 yearsof age. In some embodiments, the subject matter disclosed hereinprovides a method for treating pain, fever, or inflammation in a subjectby administering a solid dosage formulation comprising 25 mg ofrofecoxib, wherein the formulation achieves an arithmetic mean plasmaconcentration of at least about 4.6 ng/ml, 5.0 ng/ml, 5.4 ng/ml, or 5.6ng/ml at 15 minutes following single administration of the formulationto human subjects less than 65 years of age. In some embodiments, thesubject matter disclosed herein provides a method for treating pain,fever, or inflammation in a subject by administering a solid dosageformulation comprising 12.5 mg of rofecoxib, wherein the formulationachieves a mean plasma concentration of at least about 27 ng/ml, 29ng/ml, 31 ng/ml, or 33 ng/ml at 45 minutes following singleadministration of the formulation to human subjects less than 65 yearsof age. In some embodiments, the subject matter disclosed hereinprovides a method for treating pain, fever, or inflammation in a subjectby administering a solid dosage formulation comprising 12.5 mg ofrofecoxib, wherein the formulation achieves an arithmetic mean plasmaconcentration of at least about 45 ng/ml, 48 ng/ml, 51 ng/ml, 54 ng/ml,or 56 ng/ml at 45 minutes following single administration of theformulation to human subjects less than 65 years of age. In someembodiments, the subject matter disclosed herein provides a method fortreating pain, fever, or inflammation in a subject by administering asolid dosage formulation comprising 17.5 mg of rofecoxib, wherein theformulation achieves a mean plasma concentration of at least about 45ng/ml, 47 ng/ml, 49 ng/ml, or 51 ng/ml at 45 minutes following singleadministration of the formulation to human subjects less than 65 yearsof age. In some embodiments, the subject matter disclosed hereinprovides a method for treating pain, fever, or inflammation in a subjectby administering a solid dosage formulation comprising 17.5 mg ofrofecoxib, wherein the formulation achieves an arithmetic mean plasmaconcentration of at least about 74 ng/ml, 79 ng/ml, 84 ng/ml, 89 ng/ml,or 93 ng/ml at 45 minutes following single administration of theformulation to human subjects less than 65 years of age. In someembodiments, the subject matter disclosed herein provides a method fortreating pain, fever, or inflammation in a subject by administering asolid dosage formulation comprising 20 mg of rofecoxib, wherein theformulation achieves a mean plasma concentration of at least about 58ng/ml, 62 ng/ml, 66 ng/ml, 70 ng/ml, or 72 ng/ml at 45 minutes followingsingle administration of the formulation to human subjects less than 65years of age. In some embodiments, the subject matter disclosed hereinprovides a method for treating pain, fever, or inflammation in a subjectby administering a solid dosage formulation comprising 20 mg ofrofecoxib, wherein the formulation achieves an arithmetic mean plasmaconcentration of at least about 112 ng/ml, 116 ng/ml, or 121 ng/ml at 45minutes following single administration of the formulation to humansubjects less than 65 years of age. In some embodiments, the subjectmatter disclosed herein provides a method for treating pain, fever, orinflammation in a subject by administering a solid dosage formulationcomprising 25 mg of rofecoxib, wherein the formulation achieves a meanplasma concentration of at least about 78 ng/ml, 85 ng/ml, 92 ng/ml, or97 ng/ml, at 45 minutes following single administration of theformulation to human subjects less than 65 years of age. In someembodiments, the subject matter disclosed herein provides a method fortreating pain, fever, or inflammation in a subject by administering asolid dosage formulation comprising 25 mg of rofecoxib, wherein theformulation achieves an arithmetic mean plasma concentration of at leastabout 133 ng/ml, 139 ng/ml, 145 ng/ml, 151 ng/ml, or 159 ng/ml at 45minutes following single administration of the formulation to humansubjects less than 65 years of age.

In certain aspects, the subject matter disclosed herein provides a solidoral dosage form of a pharmaceutically acceptable formulation comprisinga granular component and an extragranular component, wherein thegranular component comprises an intragranular component comprisingrofecoxib or a pharmaceutically acceptable salt thereof and one or moredisintegrants, and wherein the extragranular component comprises one ormore disintegrants.

In some embodiments, the one or more disintegrants in the granularcomponent is selected from starches, clays, celluloses, algins, gums,cross-linked polymers, and combinations thereof. In some embodiments,the one or more disintegrants in the granular component is selected fromcroscarmellose, crospovidone, sodium starch glycolate, and combinationsthereof. In some embodiments, the one or more disintegrants in thegranular component is croscarmellose sodium. In some embodiments, theone or more disintegrants in the granular component is about 1% (w/w) toabout 8% (w/w) of the formulation. In some embodiments, the one or moredisintegrants in the granular component is about 1% (w/w) to about 6%(w/w) of the formulation. In some embodiments, the one or moredisintegrants in the granular component is about 1% (w/w) to about 4%(w/w) of the formulation.

In some embodiments, the one or more disintegrants in the extragranularcomponent is selected from starches, clays, celluloses, algins, gums,cross-linked polymers, and combinations thereof. In some embodiments,the one or more disintegrants in the extragranular component is selectedfrom croscarmellose, crospovidone, sodium starch glycolate, andcombinations thereof. In some embodiments, the one or more disintegrantsin the extragranular component is croscarmellose sodium. In someembodiments, the disintegrant in the extragranular component is about 1%(w/w) to about 8% (w/w) of the formulation. In some embodiments, thedisintegrant in the extragranular component is about 1% (w/w) to about6% (w/w) of the formulation. In some embodiments, the disintegrant inthe extragranular component is about 1% (w/w) to about 4% (w/w) of theformulation.

In some embodiments, the disintegrant in the granular component and thedisintegrant in the extragranular component are together about 2% (w/w)to about 12% (w/w) of the formulation. In some embodiments, thedisintegrant in the granular component and the disintegrant in theextragranular component are together about 2% (w/w) to about 10% (w/w)of the formulation. In some embodiments, the disintegrant in thegranular component and the disintegrant in the extragranular componentare together about 2% (w/w) to about 8% (w/w) of the formulation.

In some embodiments, the ratio of granular disintegrant to extragranulardisintegrant is about 40% (w/w) to about 60% (w/w). In some embodiments,the ratio of granular disintegrant to extragranular disintegrant isabout 45% (w/w) to about 55% (w/w). In some embodiments the ratio ofgranular disintegrant to extragranular disintegrant is about 50% (w/w)to about 50% (w/w). In some embodiments the ratio of granulardisintegrant to extragranular disintegrant is about 55% (w/w) to about45% (w/w). In some embodiments the ratio of granular disintegrant toextragranular disintegrant is about 60% (w/w) to about 40% (w/w).

In some embodiments, the solid oral dosage form of the pharmaceuticallyacceptable formulation further comprising one or more of a diluent, abinder, a coloring agent, and a lubricant. In some embodiments, at leasta portion of the diluent is in the granular component. In someembodiments, the diluent is selected from dicalcium phosphate, calciumsulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, drystarch, powdered sugar, sorbitol, sucrose, inositol, and combinationsthereof. In some embodiments, the diluent is selected from lactose,cellulose, or a combination thereof. In some embodiments, the diluent isselected from lactose monohydrate, microcrystalline cellulose, or acombination thereof.

In some embodiments, the lactose monohydrate is about 35% (w/w) to about45% (w/w) of the formulation. In some embodiments, the lactosemonohydrate is about 37% (w/w) to about 42% (w/w) of the formulation. Insome embodiments, the lactose monohydrate is about 39% (w/w) to about40% (w/w) of the formulation.

In some embodiments, the microcrystalline cellulose is about 35% (w/w)to about 45% (w/w) of the formulation. In some embodiments, themicrocrystalline cellulose is about 37% (w/w) to about 42% (w/w) of theformulation. In some embodiments, the microcrystalline cellulose isabout 39% (w/w) to about 40% (w/w) of the formulation.

In some embodiments, the diluent is about 75% (w/w) to about 85% (w/w)of the formulation. In some embodiments, diluent is about 77% (w/w) toabout 82% (w/w) of the formulation. In some embodiments, the diluent isabout 78% (w/w) to about 80% (w/w) of the formulation.

In some embodiments, at least a portion of the binder is in the granularcomponent. In some embodiments, the binder is selected from starches,gelatins, sugars, gums, waxes, water, alcohols, celluloses, andcombinations thereof. In some embodiments, the binder is selected fromacacia gum, tragacanth, corn starch, methyl cellulose, panwar gum,ghatti gum, mucilage of isapol husks, carboxymethylcellulose,methylcellulose, polyvinylpyrrolidone, sucrose, glucose, dextrose,molasses, lactose, and combinations thereof. In some embodiments, thebinder is hydroxypropyl cellulose. In some embodiments, the binder isabout 1% (w/w) to about 5% (w/w) of the formulation. In someembodiments, binder is about 2% (w/w) to about 4% (w/w) of theformulation. In some embodiments, the binder is about 2.5% (w/w) toabout 3.5% (w/w) of the formulation.

In some embodiments, at least a portion of the coloring agent is in theextragranular component. In some embodiments, at least a portion of thecoloring agent is in the intragranular component. In some embodiments,the coloring agent is pigment blend yellow. In some embodiments, thecoloring agent is about 0.30% (w/w) to about 0.60% (w/w) of theformulation.

In some embodiments, at least a portion of the lubricant is in theextragranular component. In some embodiments, the lubricant is selectedfrom talc, magnesium stearate, calcium stearate, stearic acid, metallicstearate, hydrogenated vegetable oils, and polyethylene glycol, cornstarch, boric acids, sodium chloride, sodium lauryl sulphate. In someembodiments, the lubricant is magnesium stearate. In some embodiments,the lubricant is about 0.10% (w/w) to about 1% (w/w) of the formulation.In some embodiments, the lubricant is about 0.50% (w/w) of theformulation.

In some embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is about 5% (w/w) to about 30% (w/w) of the formulation. In someembodiments, the rofecoxib or pharmaceutically acceptable salt thereofis about 10% (w/w) to about 20% (w/w) of the formulation. In someembodiments, the rofecoxib or pharmaceutically acceptable salt thereofis about 12% (w/w) to about 13% (w/w) of the formulation. In someembodiments, the formulation comprises about 10 mg of the rofecoxib orpharmaceutically acceptable salt thereof. In some embodiments, theformulation comprises about 10.5 mg of the rofecoxib or pharmaceuticallyacceptable salt thereof. In some embodiments, the formulation comprisesabout 11 mg of the rofecoxib or pharmaceutically acceptable saltthereof. In some embodiments, the formulation comprises about 11.5 mg ofthe rofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the formulation comprises about 12 mg of the rofecoxib orpharmaceutically acceptable salt thereof. In some embodiments, theformulation comprises about 12.5 mg of the rofecoxib or pharmaceuticallyacceptable salt thereof. In some embodiments, the formulation comprisesabout 17.5 mg of the rofecoxib or pharmaceutically acceptable saltthereof. In some embodiments, the formulation comprises about 20 mg ofthe rofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the formulation comprises about 21 mg of the rofecoxib orpharmaceutically acceptable salt thereof. In some embodiments, theformulation comprises about 22 mg of the rofecoxib or pharmaceuticallyacceptable salt thereof. In some embodiments, the formulation comprisesabout 22.5 mg of the rofecoxib or pharmaceutically acceptable saltthereof. In some embodiments, the formulation comprises about 25 mg ofthe rofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the formulation comprises about 50 mg of the rofecoxib orpharmaceutically acceptable salt thereof.

In some embodiments, the rofecoxib is highly pure. In some embodiments,the highly pure rofecoxib comprises less than about 0.1% totalimpurities. In some embodiments, the highly pure rofecoxib comprisesless than about 0.075% total impurities. In some embodiments, the highlypure rofecoxib comprises less than about 0.050% total impurities. Insome embodiments, the highly pure rofecoxib comprises less than about0.025% total impurities. In some embodiments, the highly pure rofecoxibcomprises less than about 0.001% total impurities.

In some embodiments, the highly pure rofecoxib comprises less than about0.10%, 0.05%, 0.02%, or 0.01% of4-[4-(methylsulphonyl)phenyl]-3-phenyl-2,5-furandione. In someembodiments, the highly pure rofecoxib comprises less than about 0.10%,0.05%, 0.02%, or 0.01% of4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some embodiments,the highly pure rofecoxib comprises less than about 0.10%, 0.05%, 0.02%,or 0.01% of 4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In someembodiments, the highly pure rofecoxib comprises less than about 0.10%,0.05%, 0.02%, or 0.01% of4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone.

In some embodiments, the solid oral dosage form is an oral tablet. Insome embodiments, the oral tablet provides a dissolution rate of atleast about 80% of the rofecoxib or pharmaceutically acceptable saltthereof by about 15 minutes. In some embodiments, the oral tabletprovides a dissolution rate of at least about 85% of the rofecoxib orpharmaceutically acceptable salt thereof by about 15 minutes. In someembodiments, the oral tablet provides a dissolution rate of at leastabout 90% of the rofecoxib or pharmaceutically acceptable salt thereofby about 15 minutes. In some embodiments, the oral tablet provides adissolution rate of at least about 95% of the rofecoxib orpharmaceutically acceptable salt thereof by about 15 minutes. In someembodiments, the oral tablet provides a dissolution rate of at leastabout 100% of the rofecoxib or pharmaceutically acceptable salt thereofby about 15 minutes.

In some embodiments, the dissolution rate is measured in about 1% SDS ata paddle speed of about 50 rpm and at a temperature of about 37.0°C.±0.5° C. In some embodiments, the dissolution rate is measured inabout 1% SDS at a paddle speed of about 75 rpm and at a temperature ofabout 37.0° C.±0.5° C. In some embodiments, the dissolution rate ismeasured in about 1.5% SDS at a paddle speed of about 50 rpm and at atemperature of about 37.0° C.±0.5° C. In some embodiments, thedissolution rate is measured in about 1.5% SDS at a paddle speed ofabout 75 rpm and at a temperature of about 37.0° C.±0.5° C. In someembodiments, the dissolution rate is measured in about 2% SDS at apaddle speed of about 50 rpm and at a temperature of about 37.0° C.±0.5°C. In some embodiments, the dissolution rate is measured in about 2% SDSat a paddle speed of about 75 rpm and at a temperature of about 37.0°C.±0.5° C. In some embodiments, the dissolution rate is measured using aUSP Type II apparatus. In some embodiments, the dissolution rate ismeasured with a USP Type II apparatus using 900 mL of 2% SDS, a paddlespeed of 50 rpm, and a temperature of 37.0° C.±0.5°.

In some embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 35% of thegranules are less than about 75 μm. In some embodiments, the rofecoxibor pharmaceutically acceptable salt thereof is formulated into granulesand at least about 55% of the granules are less than about 150 μm. Insome embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 75% of thegranules are less than about 250 μm. In some embodiments, the rofecoxibor pharmaceutically acceptable salt thereof is formulated into granulesand at least about 85% of the granules are less than about 425 μm. Insome embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 90% of thegranules are less than about 1000 μm.

In some embodiments, a 17.5 mg solid dosage formulation of rofecoxibreaches a median time to Cmax plasma concentration in 4 hours or lessfollowing single administration of the formulation to human subjects. Insome embodiments, a 17.5 mg solid dosage formulation of rofecoxibreaches a median time to Cmax plasma concentration in 3 hours or lessfollowing administration. In some embodiments, a 17.5 mg solid dosageformulation of rofecoxib reaches a median time to Cmax plasmaconcentration in 2.5 hours or less following administration. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib reaches amedian time to Cmax plasma concentration in 2 hours or less followingadministration. In some embodiments, a 17.5 mg solid dosage formulationof rofecoxib has a mean Cmax plasma concentration of more than 100ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean Cmax plasma concentration of more than 150 ng/ml,167 ng/ml, or 190 ng/ml. In some embodiments, a 17.5 mg solid dosageformulation of rofecoxib has a mean Cmax plasma concentration of morethan 200 ng/ml. In some embodiments, a 17.5 mg solid dosage formulationof rofecoxib has a mean Cmax plasma concentration of more than 220ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean Cmax plasma concentration of more than 250 ng/ml.In some embodiments, a 17.5 mg solid dosage formulation of rofecoxib hasa mean Cmax plasma concentration of more than 280 ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 1750 h*ng/ml. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib has a mean AUC_(0-∞) of more than2000 h*ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean AUC_(0-∞) of more than 2500 h*ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 3000 h*ng/ml. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib has a mean AUC_(0-∞) of more than3500 h*ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean AUC_(0-∞) of more than 4000 h*ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 4500 h*ng/ml. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib reaches a Cmax plasmaconcentration of least 167 ng/ml, 170 ng/ml, 175 ng/ml, 180 ng/ml, orhigher following single administration of the formulation to a humansubject. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib reaches an AUC_(0-∞) of at least 2600 h*ng/ml, 2750 h*ng/ml,2900 h*ng/ml, 3050 h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml,3650 h*ng/ml or higher following single administration of theformulation to a human subject.

In some embodiments, a 20 mg solid dosage formulation of rofecoxibreaches a median time to Cmax plasma concentration in 4 hours or lessfollowing single administration of the formulation to human subjects. Insome embodiments, a 20 mg solid dosage formulation of rofecoxib reachesa median time to Cmax plasma concentration in 3 hours or less followingadministration. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib reaches a median time to Cmax plasma concentration in 2.5hours or less following administration. In some embodiments, a 20 mgsolid dosage formulation of rofecoxib reaches a median time to Cmaxplasma concentration in 2 hours or less following administration. Insome embodiments, a 20 mg solid dosage formulation of rofecoxib has amean Cmax plasma concentration of more than 150 ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 191 ng/ml, 200 ng/ml, 215 ng/ml,or 225 ng/ml. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib has a mean Cmax plasma concentration of more than 250 ng/ml.In some embodiments, a 20 mg solid dosage formulation of rofecoxib has amean Cmax plasma concentration of more than 258 ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 300 ng/ml. In some embodiments, a20 mg solid dosage formulation of rofecoxib has a mean AUC_(0-∞) of morethan 2000 h*ng/ml. In some embodiments, a 20 mg solid dosage formulationof rofecoxib has a mean AUC_(0-∞) of more than 2500 h*ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 3000 h*ng/ml. In some embodiments, a 20 mg soliddosage formulation of rofecoxib has a mean AUC_(0-∞) of more than 3400h*ng/ml. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib has a mean AUC_(0-∞) of more than 3500 h*ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 4500 h*ng/ml. In some embodiments, a 20 mg soliddosage formulation of rofecoxib reaches a Cmax plasma concentration ofleast 190 ng/ml, 205 ng/ml, 220 ng/ml, 235 ng/ml, 250 ng/ml, or higherfollowing single administration of the formulation to a human subject.In some embodiments, a 20 mg solid dosage formulation of rofecoxibreaches an AUC_(0-∞) of at least 3000 h*ng/ml, 3200 h*ng/ml, 3350h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800 h*ng/ml, 3950 h*ng/ml, orhigher following single administration of the formulation to a humansubject. In some embodiments, the rofecoxib formulation achieves a meanCmax plasma concentration within 80% to 125% of 259 ng/ml and a meanAUC_(0-∞) within 80% to 125% of 3550 h*ng/ml. In some embodiments, therofecoxib formulation achieves a mean plasma AUC_(0-∞) of about2840-4438 h*ng/ml and a mean plasma Cmax of about 207-324 ng/mlfollowing oral administration of a single dose of the formulation to apopulation of healthy adults less than 65 years of age in a fastedstate. In some embodiments, the population of healthy adults are lessthan 60 years of age.

In some embodiments, a 25 mg solid dosage formulation of rofecoxibreaches a mean Cmax plasma concentration in less than 3 hours followingsingle administration of the formulation to human subjects. In someembodiments, a 25 mg solid dosage formulation of rofecoxib reaches amean Cmax plasma concentration in less than 2.5 hours followingadministration. In some embodiments, a 25 mg solid dosage formulation ofrofecoxib reaches a mean Cmax plasma concentration in less than 2 hoursfollowing administration. In some embodiments, a 25 mg solid dosageformulation of rofecoxib has a mean Cmax plasma concentration of morethan 240 ng/ml. In some embodiments, a 25 mg solid dosage formulation ofrofecoxib has a mean Cmax plasma concentration of more than 250 ng/ml.In some embodiments, a 25 mg solid dosage formulation of rofecoxib has amean Cmax plasma concentration of more than 300 ng/ml. In someembodiments, a 25 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 320 ng/ml. In some embodiments, a25 mg solid dosage formulation of rofecoxib has a mean AUC_(0-∞) of morethan 4250 h*ng/ml. In some embodiments, a 25 mg solid dosage formulationof rofecoxib has a mean AUC_(0-∞) of more than 4500 h*ng/ml. In someembodiments, a 25 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 4550 h*ng/ml. In some embodiments, a 25 mg soliddosage formulation of rofecoxib has a mean AUC_(0-∞) of more than 4700h*ng/ml. In some embodiments, a 25 mg solid dosage formulation ofrofecoxib reaches a mean Cmax plasma concentration of more than 240ng/ml in a median time of about 3 hours or less following administrationwith an AUC_(0-∞) of more than 4250 h*ng/ml.

In some embodiments, a solid dosage formulation of 10 mg to 50 mg ofrofecoxib achieves a mean Cmax plasma concentration from 9.8 ng/ml to 16ng/ml for each 1 mg of rofecoxib in the formulation following singleadministration of the formulation to human subjects. In someembodiments, the solid dosage formulation of rofecoxib achieves a meanCmax plasma concentration from 10 ng/ml to 14 ng/ml for each 1 mg ofrofecoxib in the formulation. In some embodiments, the solid dosageformulation of rofecoxib achieves a mean Cmax plasma concentration from10 ng/ml to 13 ng/ml for each 1 mg of rofecoxib in the formulation. Insome embodiments, the solid dosage formulation of rofecoxib achieves amean Cmax plasma concentration from 80% to 125% of 12.8 ng/ml. In someembodiments, the solid dosage formulation of rofecoxib reaches a meanAUC_(0-∞) of 170 h*ng/ml to 235 h*ng/ml for each 1 mg of rofecoxib inthe formulation. In some embodiments, the solid dosage formulation ofrofecoxib reaches a mean AUC_(0-∞) of 170 h*ng/ml to 225 h*ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, theformulation achieves a mean AUC_(0-∞) of 177 h*ng/ml to 225 h*ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, theformulation achieves a mean AUC_(0-∞) of 180 h*ng/ml to 225 h*ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, thesolid dosage formulation of rofecoxib reaches a mean AUC_(0-∞) of 190h*ng/ml to 215 h*ng/ml for each 1 mg of rofecoxib in the formulation.

In certain aspects, the subject matter disclosed herein provides a solidoral dosage form of a pharmaceutically acceptable formulation comprisinga granular component and an extragranular component, wherein thegranular component comprises an intragranular component comprising 17.5mg of rofecoxib or a pharmaceutically acceptable salt thereof. In someembodiments, the formulation achieves a median time to Cmax plasmaconcentration in 4 hours or less following single administration of theformulation to human subjects. In some embodiments, the formulationachieves a median time to Cmax plasma concentration in 3 hours or lessfollowing administration. In some embodiments, the formulation achievesa median time to Cmax plasma concentration in 2.5 hours or lessfollowing administration. In some embodiments, the formulation achievesa median time to Cmax plasma concentration in 2 hours or less followingadministration. In some embodiments, the formulation achieves a meanCmax plasma concentration of more than 100 ng/ml. In some embodiments,the formulation achieves a mean Cmax plasma concentration of more than150 ng/ml, 167 ng/ml, or 190 ng/ml. In some embodiments, the formulationachieves a mean Cmax plasma concentration of more than 200 ng/ml. Insome embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 220 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 250ng/ml. In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 280 ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 1750 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 2000h*ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞)of more than 2500 h*ng/ml. In some embodiments, the formulation achievesa mean AUC_(0-∞) of more than 3000 h*ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 3100 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 3500h*ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞)of more than 4000 h*ng/ml. In some embodiments, the formulation achievesa mean AUC_(0-∞) of more than 4500 h*ng/ml. In some embodiments, theformulation reaches a Cmax plasma concentration of least 167 ng/ml, 170ng/ml, 175 ng/ml, 180 ng/ml, or higher following single administrationof the formulation to a human subject. In some embodiments, theformulation reaches an AUC_(0-∞) of at least 2600 h*ng/ml, 2750 h*ng/ml,2900 h*ng/ml, 3050 h*ng/ml, 3100 h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml,3500 h*ng/ml, 3650 h*ng/ml or higher following single administration ofthe formulation to a human subject.

In certain aspects, the subject matter disclosed herein provides a solidoral dosage form of a pharmaceutically acceptable formulation comprisinga granular component and an extragranular component, wherein thegranular component comprises an intragranular component comprising 20 mgof rofecoxib or a pharmaceutically acceptable salt thereof. In someembodiments, the formulation achieves a median time to Cmax plasmaconcentration in 4 hours or less following single administration of theformulation to human subjects. In some embodiments, the formulationachieves a median time to Cmax plasma concentration in 3 hours or lessfollowing administration. In some embodiments, the formulation achievesa median time to Cmax plasma concentration in 2.5 hours or lessfollowing administration. In some embodiments, the formulation achievesa median time to Cmax plasma concentration in 2 hours or less followingadministration. In some embodiments, the formulation achieves a meanCmax plasma concentration of more than 150 ng/ml. In some embodiments,the formulation achieves a mean Cmax plasma concentration of more than191 ng/ml, 200 ng/ml, 215 ng/ml, or 225 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 250ng/ml. In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 258 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 300ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞) ofmore than 2000 h*ng/ml. In some embodiments, the formulation achieves amean AUC_(0-∞) of more than 2500 h*ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 3000 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 3400h*ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞)of more than 3500 h*ng/ml. In some embodiments, the formulation achievesa mean AUC_(0-∞) of more than 4000 h*ng/ml. In some embodiments, theformulation reaches a Cmax plasma concentration of least 190 ng/ml, 205ng/ml, 220 ng/ml, 235 ng/ml, 250 ng/ml, or higher following singleadministration of the formulation to a human subject. In someembodiments, the formulation reaches an AUC_(0-∞) of at least 3000h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800h*ng/ml, 3950 h*ng/ml, or higher following single administration of theformulation to a human subject. In some embodiments, the rofecoxibformulation achieves a mean Cmax plasma concentration within 80% to 125%of 259 ng/ml and a mean AUC_(0-∞) within 80% to 125% of 3550 h*ng/ml. Insome embodiments, the rofecoxib formulation achieves a mean plasmaAUC_(0-∞) of about 2840-4438 h*ng/ml and a mean plasma Cmax of about207-324 ng/ml following oral administration of a single dose of theformulation to a population of healthy adults less than 65 years of agein a fasted state. In some embodiments, the population of healthy adultsare less than 60 years of age.

In certain aspects, the subject matter disclosed herein provides a solidoral dosage form of a pharmaceutically acceptable formulation comprisinga granular component and an extragranular component, wherein thegranular component comprises an intragranular component comprising 25 mgof rofecoxib or a pharmaceutically acceptable salt thereof. In someembodiments, the formulation achieves a mean Cmax plasma concentrationin less than 3 hours following single administration of the formulationto human subjects. In some embodiments, the formulation achieves a meanCmax plasma concentration in less than 2.5 hours followingadministration. In some embodiments, the formulation achieves a meanCmax plasma concentration in less than 2 hours following administration.In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 240 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 300ng/ml. In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 320 ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 4250 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 4500h*ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞)of more than 4550 h*ng/ml. In some embodiments, the formulation achievesa mean AUC_(0-∞) of more than 4700 h*ng/ml. In some embodiments, theformulation achieves a Cmax plasma concentration of more than 240 ng/mlin about 3 hours following administration with an AUC_(0-∞) of more than4250 h*ng/ml.

The subject matter disclosed herein provides a solid oral dosage form ofa pharmaceutically acceptable formulation comprising a granularcomponent and an extragranular component, wherein the granular componentcomprises an intragranular component comprising 10 mg to 50 mg ofrofecoxib or a pharmaceutically acceptable salt thereof that achieves amean Cmax plasma concentration from 9.8 ng/ml to 16 ng/ml for each 1 mgof rofecoxib in the formulation following single administration of theformulation to human subjects. In some embodiments, the solid dosageformulation of rofecoxib achieves a mean Cmax plasma concentration from10 ng/ml to 14 ng/ml for each 1 mg of rofecoxib in the formulation. Insome embodiments, the solid dosage formulation of rofecoxib achieves amean Cmax plasma concentration from 10 ng/ml to 13 ng/ml for each 1 mgof rofecoxib in the formulation. In some embodiments, the solid dosageformulation of rofecoxib achieves a mean Cmax plasma concentration from80% to 125% of 12.8 ng/ml. In some embodiments, the solid dosageformulation of rofecoxib reaches a mean AUC_(0-∞) of 170 h*ng/ml to 235h*ng/ml for each 1 mg of rofecoxib in the formulation. In someembodiments, the solid dosage formulation of rofecoxib reaches a meanAUC_(0-∞) of 170 h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib inthe formulation. In some embodiments, the formulation achieves a meanAUC_(0-∞) of 177 h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib inthe formulation. In some embodiments, the formulation achieves a meanAUC_(0-∞) of 180 h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib inthe formulation. In some embodiments, the solid dosage formulation ofrofecoxib reaches a mean AUC_(0-∞) of 190 h*ng/ml to 215 h*ng/ml foreach 1 mg of rofecoxib in the formulation.

A method for inhibiting COX-2 in a subject in need thereof, the methodcomprising administering to the subject a pharmaceutically acceptableformulation comprising a granular component and an extragranularcomponent, wherein the granular component comprises an intragranularcomponent comprising rofecoxib or a pharmaceutically acceptable saltthereof and one or more disintegrants, and wherein the extragranularcomponent comprises one or more disintegrants.

In some embodiments, the one or more disintegrants in the granularcomponent is selected from starches, clays, celluloses, algins, gums,cross-linked polymers, and combinations thereof. In some embodiments,the one or more disintegrants in the granular component is selected fromcroscarmellose, crospovidone, sodium starch glycolate, and combinationsthereof. In some embodiments, the one or more disintegrants in thegranular component is croscarmellose sodium. In some embodiments, theone or more disintegrants in the granular component is about 1% (w/w) toabout 8% (w/w) of the formulation. In some embodiments, the one or moredisintegrants in the granular component is about 1% (w/w) to about 6%(w/w) of the formulation. In some embodiments, the one or moredisintegrants in the granular component is about 1% (w/w) to about 4%(w/w) of the formulation.

In some embodiments, the one or more disintegrants in the extragranularcomponent is selected from starches, clays, celluloses, algins, gums,cross-linked polymers, and combinations thereof. In some embodiments,the one or more disintegrants in the extragranular component is selectedfrom croscarmellose, crospovidone, sodium starch glycolate, andcombinations thereof. In some embodiments, the one or more disintegrantsin the extragranular component is croscarmellose sodium. In someembodiments, the disintegrant in the extragranular component is about 1%(w/w) to about 8% (w/w) of the formulation. In some embodiments, thedisintegrant in the extragranular component is about 1% (w/w) to about6% (w/w) of the formulation. In some embodiments, the disintegrant inthe extragranular component is about 1% (w/w) to about 4% (w/w) of theformulation.

In some embodiments, the disintegrant in the granular component and thedisintegrant in the extragranular component are together about 2% (w/w)to about 12% (w/w) of the formulation. In some embodiments, thedisintegrant in the granular component and the disintegrant in theextragranular component are together about 2% (w/w) to about 10% (w/w)of the formulation. In some embodiments, the disintegrant in thegranular component and the disintegrant in the extragranular componentare together about 2% (w/w) to about 8% (w/w) of the formulation.

In some embodiments, the ratio of granular disintegrant to extragranulardisintegrant is about 40% (w/w) to about 60% (w/w). In some embodiments,the ratio of granular disintegrant to extragranular disintegrant isabout 45% (w/w) to about 55% (w/w). In some embodiments, the ratio ofgranular disintegrant to extragranular disintegrant is about 50% (w/w)to about 50% (w/w). In some embodiments, the ratio of granulardisintegrant to extragranular disintegrant is about 55% (w/w) to about45% (w/w). In some embodiments the ratio of granular disintegrant toextragranular disintegrant is about 60% (w/w) to about 40% (w/w).

In some embodiments, the pharmaceutically acceptable formulation furthercomprises one or more of a diluent, a binder, a coloring agent, and alubricant. In some embodiments, at least a portion of the diluent is inthe granular component. In some embodiments, the diluent is selectedfrom dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin,mannitol, sodium chloride, dry starch, powdered sugar, sorbitol,sucrose, inositol, and combinations thereof. In some embodiments, thediluent is selected from lactose, cellulose, or a combination thereof.In some embodiments, the diluent is selected from lactose monohydrate,microcrystalline cellulose, or a combination thereof.

In some embodiments, the lactose monohydrate is about 35% (w/w) to about45% (w/w) of the formulation. In some embodiments, the lactosemonohydrate is about 37% (w/w) to about 42% (w/w) of the formulation. Insome embodiments, the lactose monohydrate is about 39% (w/w) to about40% (w/w) of the formulation.

In some embodiments, the microcrystalline cellulose is about 35% (w/w)to about 45% (w/w) of the formulation. In some embodiments, themicrocrystalline cellulose is about 37% (w/w) to about 42% (w/w) of theformulation. In some embodiments, the microcrystalline cellulose isabout 39% (w/w) to about 40% (w/w) of the formulation.

In some embodiments, the diluent is about 75% (w/w) to about 85% (w/w)of the formulation. In some embodiments, diluent is about 77% (w/w) toabout 82% (w/w) of the formulation. In some embodiments, the diluent isabout 78% (w/w) to about 80% (w/w) of the formulation.

In some embodiments, at least a portion of the binder is in the granularcomponent. In some embodiments, the binder is selected from starches,gelatins, sugars, gums, waxes, water, alcohols, celluloses, andcombinations thereof. In some embodiments, the binder is selected fromacacia gum, tragacanth, corn starch, methyl cellulose, panwar gum,ghatti gum, mucilage of isapol husks, carboxymethylcellulose,methylcellulose, polyvinylpyrrolidone, sucrose, glucose, dextrose,molasses, lactose, and combinations thereof. In some embodiments, thebinder is hydroxypropyl cellulose. In some embodiments, the binder isabout 1% (w/w) to about 5% (w/w) of the formulation. In someembodiments, binder is about 2% (w/w) to about 4% (w/w) of theformulation. In some embodiments, the binder is about 2.5% (w/w) toabout 3.5% (w/w) of the formulation.

In some embodiments, at least a portion of the coloring agent is in theextragranular component. In some embodiments, the coloring agent ispigment blend yellow. In some embodiments, the coloring agent is about0.30% (w/w) to about 0.60% (w/w) of the formulation.

In some embodiments, at least a portion of the lubricant is in theextragranular component. In some embodiments, the lubricant is selectedfrom talc, magnesium stearate, calcium stearate, stearic acid, metallicstearate, hydrogenated vegetable oils, and polyethylene glycol, cornstarch, boric acids, sodium chloride, sodium lauryl sulphate. In someembodiments, the lubricant is magnesium stearate. In some embodiments,the lubricant is about 0.10% (w/w) to about 1% (w/w) of the formulation.In some embodiments, the lubricant is about 0.50% (w/w) of theformulation.

In some embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is about 5% (w/w) to about 30% (w/w) of the formulation. In someembodiments, the rofecoxib or pharmaceutically acceptable salt thereofis about 10% (w/w) to about 20% (w/w) of the formulation. In someembodiments, the rofecoxib or pharmaceutically acceptable salt thereofis about 12% (w/w) to about 13% (w/w) of the formulation. In someembodiments, the formulation comprises about 10 mg of the rofecoxib orpharmaceutically acceptable salt thereof. In some embodiments, theformulation comprises about 10.5 mg of the rofecoxib or pharmaceuticallyacceptable salt thereof. In some embodiments, the formulation comprisesabout 11 mg of the rofecoxib or pharmaceutically acceptable saltthereof. In some embodiments, the formulation comprises about 11.5 mg ofthe rofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the formulation comprises about 12 mg of the rofecoxib orpharmaceutically acceptable salt thereof. In some embodiments, theformulation comprises about 12.5 mg of the rofecoxib or pharmaceuticallyacceptable salt thereof. In some embodiments, the formulation comprisesabout 17.5 mg of the rofecoxib or pharmaceutically acceptable saltthereof. In some embodiments, the formulation comprises about 20 mg ofthe rofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the formulation comprises about 21 mg of the rofecoxib orpharmaceutically acceptable salt thereof. In some embodiments, theformulation comprises about 22 mg of the rofecoxib or pharmaceuticallyacceptable salt thereof. In some embodiments, the formulation comprisesabout 22.5 mg of the rofecoxib or pharmaceutically acceptable saltthereof. In some embodiments, the formulation comprises about 25 mg ofthe rofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the formulation comprises about 50 mg of the rofecoxib orpharmaceutically acceptable salt thereof.

In some embodiments, the rofecoxib is highly pure. In some embodiments,the highly pure rofecoxib comprises less than about 0.1% totalimpurities. In some embodiments, the highly pure rofecoxib comprisesless than about 0.075% total impurities. In some embodiments, the highlypure rofecoxib comprises less than about 0.050% total impurities. Insome embodiments, the highly pure rofecoxib comprises less than about0.025% total impurities. In some embodiments, the highly pure rofecoxibcomprises less than about 0.001% total impurities.

In some embodiments, the highly pure rofecoxib comprises less than about0.10%, 0.05%, 0.02%, or 0.01% of4-[4-(methylsulphonyl)phenyl]-3-phenyl-2,5-furandione. In someembodiments, the highly pure rofecoxib comprises less than about 0.10%,0.05%, 0.02%, or 0.01% of4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some embodiments,the highly pure rofecoxib comprises less than about 0.10%, 0.05%, 0.02%,or 0.01% of 4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In someembodiments, the highly pure rofecoxib comprises less than about 0.10%,0.05%, 0.02%, or 0.01% of4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone.

In some embodiments, the formulation is suitable for oraladministration. In some embodiments, the formulation is a solid dosageform. In some embodiments, the solid dosage form is an oral tablet. Insome embodiments, the oral tablet provides a dissolution rate of atleast about 80% of the rofecoxib or pharmaceutically acceptable saltthereof by about 15 minutes. In some embodiments, the oral tabletprovides a dissolution rate of at least about 85% of the rofecoxib orpharmaceutically acceptable salt thereof by about 15 minutes. In someembodiments, the oral tablet provides a dissolution rate of at leastabout 90% of the rofecoxib or pharmaceutically acceptable salt thereofby about 15 minutes. In some embodiments, the oral tablet provides adissolution rate of at least about 95% of the rofecoxib orpharmaceutically acceptable salt thereof by about 15 minutes. In someembodiments, the oral tablet provides a dissolution rate of at leastabout 100% of the rofecoxib or pharmaceutically acceptable salt thereofby about 15 minutes.

In some embodiments, the dissolution rate is measured in about 1% SDS ata paddle speed of about 50 rpm and at a temperature of about 37.0°C.±0.5° C. In some embodiments, the dissolution rate is measured inabout 1% SDS at a paddle speed of about 75 rpm and at a temperature ofabout 37.0° C.±0.5° C. In some embodiments, the dissolution rate ismeasured in about 1.5% SDS at a paddle speed of about 50 rpm and at atemperature of about 37.0° C.±0.5° C. In some embodiments, thedissolution rate is measured in about 1.5% SDS at a paddle speed ofabout 75 rpm and at a temperature of about 37.0° C.±0.5° C. In someembodiments, the dissolution rate is measured in about 2% SDS at apaddle speed of about 50 rpm and at a temperature of about 37.0° C.±0.5°C. In some embodiments, the dissolution rate is measured in about 2% SDSat a paddle speed of about 75 rpm and at a temperature of about 37.0°C.±0.5° C. In some embodiments, the dissolution rate is measured using aUSP Type II apparatus. In some embodiments, the dissolution rate ismeasured with a USP Type II apparatus using 900 mL of 2% SDS, a paddlespeed of 50 rpm, and a temperature of 37.0° C.±0.5°.

In some embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 35% of thegranules are less than about 75 μm. In some embodiments, the rofecoxibor pharmaceutically acceptable salt thereof is formulated into granulesand at least about 55% of the granules are less than about 150 μm. Insome embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 75% of thegranules are less than about 250 μm. In some embodiments, the rofecoxibor pharmaceutically acceptable salt thereof is formulated into granulesand at least about 85% of the granules are less than about 425 μm. Insome embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 90% of thegranules are less than about 1000 μm.

In some embodiments, a 17.5 mg solid dosage formulation of rofecoxibreaches a median time to Cmax plasma concentration in 4 hours or lessfollowing single administration of the formulation to human subjects. Insome embodiments, a 17.5 mg solid dosage formulation of rofecoxibreaches a median time to Cmax plasma concentration in 3 hours or lessfollowing administration. In some embodiments, a 17.5 mg solid dosageformulation of rofecoxib reaches a median time to Cmax plasmaconcentration in 2.5 hours or less following administration. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib reaches amedian time to Cmax plasma concentration in 2 hours or less followingadministration. In some embodiments, a 17.5 mg solid dosage formulationof rofecoxib has a mean Cmax plasma concentration of more than 100ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean Cmax plasma concentration of more than 150 ng/ml,167 ng/ml, or 190 ng/ml. In some embodiments, a 17.5 mg solid dosageformulation of rofecoxib has a mean Cmax plasma concentration of morethan 200 ng/ml. In some embodiments, a 17.5 mg solid dosage formulationof rofecoxib has a mean Cmax plasma concentration of more than 220ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean Cmax plasma concentration of more than 250 ng/ml.In some embodiments, a 17.5 mg solid dosage formulation of rofecoxib hasa mean Cmax plasma concentration of more than 280 ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 1750 h*ng/ml. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib has a mean AUC_(0-∞) of more than2000 h*ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean AUC_(0-∞) of more than 2500 h*ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 3000 h*ng/ml. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib has a mean AUC_(0-∞) of more than3100 h*ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean AUC_(0-∞) of more than 3500 h*ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 4000 h*ng/ml. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib has a mean AUC_(0-∞) of more than4500 h*ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib reaches a Cmax plasma concentration of least 167 ng/ml, 170ng/ml, 175 ng/ml, 180 ng/ml, or higher following single administrationof the formulation to a human subject. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib reaches an AUC_(0-∞) of at least2600 h*ng/ml, 2750 h*ng/ml, 2900 h*ng/ml, 3050 h*ng/ml, 3100 h*ng/ml,3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml or higherfollowing single administration of the formulation to a human subject.

In some embodiments, a 20 mg solid dosage formulation of rofecoxibreaches a median time to Cmax plasma concentration in 4 hours or lessfollowing single administration of the formulation to human subjects. Insome embodiments, a 20 mg solid dosage formulation of rofecoxib reachesa median time to Cmax plasma concentration in 3 hours or less followingadministration. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib reaches a median time to Cmax plasma concentration in 2.5hours or less following administration. In some embodiments, a 20 mgsolid dosage formulation of rofecoxib reaches a median time to Cmaxplasma concentration in 2 hours or less following administration. Insome embodiments, a 20 mg solid dosage formulation of rofecoxib has amean Cmax plasma concentration of more than 150 ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 191 ng/ml, 200 ng/ml, 215 ng/ml,or 225 ng/ml. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib has a mean Cmax plasma concentration of more than 250 ng/ml.In some embodiments, a 20 mg solid dosage formulation of rofecoxib has amean Cmax plasma concentration of more than 258 ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 300 ng/ml. In some embodiments, a20 mg solid dosage formulation of rofecoxib has a mean AUC_(0-∞) of morethan 2000 h*ng/ml. In some embodiments, a 20 mg solid dosage formulationof rofecoxib has a mean AUC_(0-∞) of more than 2500 h*ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 3000 h*ng/ml. In some embodiments, a 20 mg soliddosage formulation of rofecoxib has a mean AUC_(0-∞) of more than 3400h*ng/ml. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib has a mean AUC_(0-∞) of more than 3500 h*ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 4000 h*ng/ml. In some embodiments, a 20 mg soliddosage formulation of rofecoxib reaches a Cmax plasma concentration ofleast 190 ng/ml, 205 ng/ml, 220 ng/ml, 235 ng/ml, 250 ng/ml, or higherfollowing single administration of the formulation to a human subject.In some embodiments, a 20 mg solid dosage formulation of rofecoxibreaches an AUC_(0-∞) of at least 3000 h*ng/ml, 3200 h*ng/ml, 3350h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800 h*ng/ml, 3950 h*ng/ml, orhigher following single administration of the formulation to a humansubject. In some embodiments, the rofecoxib formulation achieves a meanCmax plasma concentration within 80% to 125% of 259 ng/ml and a meanAUC_(0-∞) within 80% to 125% of 3550 h*ng/ml. In some embodiments, therofecoxib formulation achieves a mean plasma AUC_(0-∞) of about2840-4438 h*ng/ml and a mean plasma Cmax of about 207-324 ng/mlfollowing oral administration of a single dose of the formulation to apopulation of healthy adults less than 65 years of age in a fastedstate. In some embodiments, the population of healthy adults are lessthan 60 years of age.

In some embodiments, a 25 mg solid dosage formulation of rofecoxibreaches a mean Cmax plasma concentration in less than 3 hours followingsingle administration of the formulation to human subjects. In someembodiments, a 25 mg solid dosage formulation of rofecoxib reaches amean Cmax plasma concentration in less than 2.5 hours followingadministration. In some embodiments, a 25 mg solid dosage formulation ofrofecoxib reaches a mean Cmax plasma concentration in less than 2 hoursfollowing administration. In some embodiments, a 25 mg solid dosageformulation of rofecoxib has a mean Cmax plasma concentration of morethan 240 ng/ml. In some embodiments, a 25 mg solid dosage formulation ofrofecoxib has a mean Cmax plasma concentration of more than 250 ng/ml.In some embodiments, a 25 mg solid dosage formulation of rofecoxib has amean Cmax plasma concentration of more than 300 ng/ml. In someembodiments, a 25 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 320 ng/ml. In some embodiments, a25 mg solid dosage formulation of rofecoxib has a mean AUC_(0-∞) of morethan 4250 h*ng/ml. In some embodiments, a 25 mg solid dosage formulationof rofecoxib has a mean AUC_(0-∞) of more than 4500 h*ng/ml. In someembodiments, a 25 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 4700 h*ng/ml. In some embodiments, a 25 mg soliddosage formulation of rofecoxib has a mean AUC_(0-∞) of more than 5000h*ng/ml. In some embodiments, a 25 mg solid dosage formulation ofrofecoxib reaches a Cmax plasma concentration of more than 240 ng/ml ina median time of about 3 hours or less following administration with anAUC_(0-∞) of more than 4250 h*ng/ml.

In some embodiments, a 10 mg to 50 mg solid dosage formulation ofrofecoxib achieves a mean Cmax plasma concentration from 9.8 ng/ml to 16ng/ml for each 1 mg of rofecoxib in the formulation following singleadministration of the formulation to human subjects. In someembodiments, the solid dosage formulation of rofecoxib achieves a meanCmax plasma concentration from 10 ng/ml to 14 ng/ml for each 1 mg ofrofecoxib in the formulation. In some embodiments, the solid dosageformulation of rofecoxib achieves a mean Cmax plasma concentration from10 ng/ml to 13 ng/ml for each 1 mg of rofecoxib in the formulation. Insome embodiments, the solid dosage formulation of rofecoxib achieves amean Cmax plasma concentration from 80% to 125% of 12.8 ng/ml. In someembodiments, the solid dosage formulation of rofecoxib reaches a meanAUC_(0-∞) of 170 h*ng/ml to 235 h*ng/ml for each 1 mg of rofecoxib inthe formulation. In some embodiments, the solid dosage formulation ofrofecoxib reaches a mean AUC_(0-∞) of 170 h*ng/ml to 225 h*ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, theformulation achieves a mean AUC_(0-∞) of 177 h*ng/ml to 225 h*ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, theformulation achieves a mean AUC_(0-∞) of 180 h*ng/ml to 225 h*ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, thesolid dosage formulation of rofecoxib reaches a mean AUC_(0-∞) of 190h*ng/ml to 215 h*ng/ml for each 1 mg of rofecoxib in the formulation.

In certain aspects, the subject matter disclosed herein provides amethod for inhibiting COX-2 in a subject in need thereof, the methodcomprising administering to the subject a solid dosage formulationcomprising 17.5 mg of rofecoxib or a pharmaceutically acceptable saltthereof. In some embodiments, the formulation achieves a median time toCmax plasma concentration in 4 hours or less following singleadministration of the formulation to human subjects. In someembodiments, the formulation achieves a median time to Cmax plasmaconcentration in 3 hours or less following administration. In someembodiments, the formulation achieves a median time to Cmax plasmaconcentration in 2.5 hours or less following administration. In someembodiments, the formulation achieves a median time to Cmax plasmaconcentration in 2 hours or less following administration. In someembodiments, the formulation achieves a mean Cmax plasma concentrationof more than 100 ng/ml. In some embodiments, the formulation achieves amean Cmax plasma concentration of more than 150 ng/ml, 167 ng/ml, or 190ng/ml. In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 200 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 220ng/ml. In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 250 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 280ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞) ofmore than 1750 h*ng/ml. In some embodiments, the formulation achieves amean AUC_(0-∞) of more than 2000 h*ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 2500 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 3000h*ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞)of more than 3500 h*ng/ml. In some embodiments, the formulation achievesa mean AUC_(0-∞) of more than 4000 h*ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 4500 h*ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib reaches aCmax plasma concentration of least 167 ng/ml, 170 ng/ml, 175 ng/ml, 180ng/ml, or higher following single administration of the formulation to ahuman subject. In some embodiments, a 17.5 mg solid dosage formulationof rofecoxib reaches an AUC_(0-∞) of at least 2600 h*ng/ml, 2750h*ng/ml, 2900 h*ng/ml, 3050 h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml, 3500h*ng/ml, 3650 h*ng/ml or higher following single administration of theformulation to a human subject.

In certain aspects, the subject matter disclosed herein provides amethod for inhibiting COX-2 in a subject in need thereof, the methodcomprising administering to the subject a solid dosage formulationcomprising 20 mg of rofecoxib or a pharmaceutically acceptable saltthereof. In some embodiments, the formulation achieves a median time toCmax plasma concentration in 4 hours or less following singleadministration of the formulation to human subjects. In someembodiments, the formulation achieves a median time to Cmax plasmaconcentration in 3 hours or less following administration. In someembodiments, the formulation achieves a mean Cmax plasma concentrationin less than 3 hours following administration. In some embodiments, theformulation achieves a median time to Cmax plasma concentration in 2.5hours or less following administration. In some embodiments, theformulation achieves a median time to Cmax plasma concentration in 2hours or less following administration. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 150ng/ml. In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 191 ng/ml, 200 ng/ml, 215 ng/ml, or 225ng/ml. In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 250 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 258ng/ml. In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 300 ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 2000 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 2500h*ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞)of more than 3000 h*ng/ml. In some embodiments, the formulation achievesa mean AUC_(0-∞) of more than 3400 h*ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 3500 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 4000h*ng/ml. In some embodiments, the formulation reaches a Cmax plasmaconcentration of least 190 ng/ml, 205 ng/ml, 220 ng/ml, 235 ng/ml, 250ng/ml, or higher following single administration of the formulation to ahuman subject. In some embodiments, the formulation reaches an AUC_(0-∞)of at least 3000 h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650h*ng/ml, 3800 h*ng/ml, 3950 h*ng/ml, or higher following singleadministration of the formulation to a human subject.

In certain aspects, the subject matter disclosed herein provides amethod for inhibiting COX-2 in a subject in need thereof, the methodcomprising administering to the subject a solid dosage formulationcomprising 25 mg of rofecoxib or a pharmaceutically acceptable saltthereof. In some embodiments, the formulation achieves a mean Cmaxplasma concentration in less than 3 hours following singleadministration of the formulation to human subjects. In someembodiments, the formulation achieves a mean Cmax plasma concentrationin less than 2.5 hours following administration. In some embodiments,the formulation achieves a mean Cmax plasma concentration in less than 2hours following administration. In some embodiments, the formulationachieves a mean Cmax plasma concentration of more than 240 ng/ml. Insome embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 250 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 300ng/ml. In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 320 ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 4250 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 4500h*ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞)of more than 4550 h*ng/ml. In some embodiments, the formulation achievesa mean AUC_(0-∞) of more than 4700 h*ng/ml. In some embodiments, theformulation achieves a Cmax plasma concentration of more than 240 ng/mlabout 3 hours following administration with an AUC_(0-∞) of more than4250 h*ng/ml.

In certain aspects, the subject matter disclosed herein provides amethod for inhibiting COX-2 in a subject in need thereof, the methodcomprising administering to the subject a solid dosage formulationcomprising 10 mg to 50 mg of rofecoxib or a pharmaceutically acceptablesalt thereof. In some embodiments, the formulation achieves a mean Cmaxplasma concentration from 9.8 ng/ml to 16 ng/ml for each 1 mg ofrofecoxib in the formulation following single administration of theformulation to human subjects. In some embodiments, the formulation ofrofecoxib achieves a mean Cmax plasma concentration from 10 ng/ml to 14ng/ml for each 1 mg of rofecoxib in the formulation. In someembodiments, the formulation of rofecoxib achieves a mean Cmax plasmaconcentration from 10 ng/ml to 13 ng/ml for each 1 mg of rofecoxib inthe formulation. In some embodiments, the solid dosage formulation ofrofecoxib achieves a mean Cmax plasma concentration from 80% to 125% of12.8 ng/ml. In some embodiments, the formulation of rofecoxib reaches amean AUC_(0-∞) of 170 h*ng/ml to 235 h*ng/ml for each 1 mg of rofecoxibin the formulation. In some embodiments, the formulation of rofecoxibreaches a mean AUC_(0-∞) of 170 h*ng/ml to 225 h*ng/ml for each 1 mg ofrofecoxib in the formulation. In some embodiments, the formulationachieves a mean AUC_(0-∞) of 177 h*ng/ml to 225 h*ng/ml for each 1 mg ofrofecoxib in the formulation. In some embodiments, the formulationachieves a mean AUC_(0-∞) of 180 h*ng/ml to 225 h*ng/ml for each 1 mg ofrofecoxib in the formulation. In some embodiments, the formulation ofrofecoxib reaches a mean AUC_(0-∞) of 190 h*ng/ml to 215 h*ng/ml foreach 1 mg of rofecoxib in the formulation.

In certain aspects, a method is provided for inhibiting COX-2 inpatients within a patient population, the method comprising providing asolid dosage formulation comprising 10 mg to 50 mg of rofecoxib to thepatient population, wherein the formulation achieves a mean Cmax plasmaconcentration from 9.8 ng/ml to 16 ng/ml for each 1 mg of rofecoxib inthe formulation following single administration of the formulation tothe patients within the patient population. In some embodiments, thesolid dosage formulation of rofecoxib achieves a mean Cmax plasmaconcentration from 10 ng/ml to 14 ng/ml for each 1 mg of rofecoxib inthe formulation. In some embodiments, the solid dosage formulation ofrofecoxib achieves a mean Cmax plasma concentration from 10 ng/ml to 13ng/ml for each 1 mg of rofecoxib in the formulation. In someembodiments, the solid dosage formulation of rofecoxib achieves a meanCmax plasma concentration from 80% to 125% of 12.8 ng/ml. In someembodiments, the solid dosage formulation of rofecoxib reaches a meanAUC_(0-∞) of 170 h*ng/ml to 235 h*ng/ml for each 1 mg of rofecoxib inthe formulation. In some embodiments, the solid dosage formulation ofrofecoxib reaches a mean AUC_(0-∞) of 170 h*ng/ml to 225 h*ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, theformulation achieves a mean AUC_(0-∞) of 177 h*ng/ml to 225 h*ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, theformulation achieves a mean AUC_(0-∞) of 180 h*ng/ml to 225 h*ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, thesolid dosage formulation of rofecoxib reaches a mean AUC_(0-∞) of 190h*ng/ml to 215 h*ng/ml for each 1 mg of rofecoxib in the formulation.

A method for inhibiting COX-2 in a subject in need thereof, the methodcomprising administering to the subject a solid dosage form comprising agranular component and an extragranular component, wherein the granularcomponent comprises an intragranular component comprising rofecoxib or apharmaceutically acceptable salt thereof and one or more disintegrants,and wherein the extragranular component comprises one or moredisintegrants.

In some embodiments, the one or more disintegrants in the granularcomponent is selected from starches, clays, celluloses, algins, gums,cross-linked polymers, and combinations thereof. In some embodiments,the one or more disintegrants in the granular component is selected fromcroscarmellose, crospovidone, sodium starch glycolate, and combinationsthereof.

In some embodiments, the one or more disintegrants in the granularcomponent is croscarmellose sodium. In some embodiments, the one or moredisintegrants in the granular component is about 1% (w/w) to about 8%(w/w) of the solid dosage form. In some embodiments, the one or moredisintegrants in the granular component is about 1% (w/w) to about 6%(w/w) of the solid dosage form. In some embodiments, the one or moredisintegrants in the granular component is about 1% (w/w) to about 4%(w/w) of the solid dosage form.

In some embodiments, the one or more disintegrants in the extragranularcomponent is selected from starches, clays, celluloses, algins, gums,cross-linked polymers, and combinations thereof. In some embodiments,the one or more disintegrants in the extragranular component is selectedfrom croscarmellose, crospovidone, sodium starch glycolate, andcombinations thereof. In some embodiments, the one or more disintegrantsin the extragranular component is croscarmellose sodium. In someembodiments, the disintegrant in the extragranular component is about 1%(w/w) to about 8% (w/w) of the solid dosage form. In some embodiments,the disintegrant in the extragranular component is about 1% (w/w) toabout 6% (w/w) of the solid dosage form. In some embodiments, thedisintegrant in the extragranular component is about 1% (w/w) to about4% (w/w) of the solid dosage form.

In some embodiments, the disintegrant in the granular component and thedisintegrant in the extragranular component are together about 2% (w/w)to about 12% (w/w) of the solid dosage form. In some embodiments, thedisintegrant in the granular component and the disintegrant in theextragranular component are together about 2% (w/w) to about 10% (w/w)of the solid dosage form. In some embodiments, the disintegrant in thegranular component and the disintegrant in the extragranular componentare together about 2% (w/w) to about 8% (w/w) of the solid dosage form.

In some embodiments, the ratio of granular disintegrant to extragranulardisintegrant is about 40% (w/w) to about 60% (w/w). In some embodiments,the ratio of granular disintegrant to extragranular disintegrant isabout 45% (w/w) to about 55% (w/w). In some embodiments, the ratio ofgranular disintegrant to extragranular disintegrant is about 50% (w/w)to about 50% (w/w). In some embodiments, the ratio of granulardisintegrant to extragranular disintegrant is about 55% (w/w) to about45% (w/w). In some embodiments, the ratio of granular disintegrant toextragranular disintegrant is about 60% (w/w) to about 40% (w/w).

In some embodiments, the solid dosage form further comprising one ormore of a diluent, a binder, a coloring agent, and a lubricant. In someembodiments, at least a portion of the diluent is in the granularcomponent. In some embodiments, the diluent is selected from dicalciumphosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodiumchloride, dry starch, powdered sugar, sorbitol, sucrose, inositol, andcombinations thereof. In some embodiments, the diluent is selected fromlactose, cellulose, or a combination thereof. In some embodiments, thediluent is selected from lactose monohydrate, microcrystallinecellulose, or a combination thereof.

In some embodiments, the lactose monohydrate is about 35% (w/w) to about45% (w/w) of the solid dosage form. In some embodiments, the lactosemonohydrate is about 37% (w/w) to about 42% (w/w) of the solid dosageform. In some embodiments, the lactose monohydrate is about 39% (w/w) toabout 40% (w/w) of the solid dosage form.

In some embodiments, the microcrystalline cellulose is about 35% (w/w)to about 45% (w/w) of the solid dosage form. In some embodiments, themicrocrystalline cellulose is about 37% (w/w) to about 42% (w/w) of thesolid dosage form. In some embodiments, the microcrystalline celluloseis about 39% (w/w) to about 40% (w/w) of the solid dosage form.

In some embodiments, the diluent is about 75% (w/w) to about 85% (w/w)of the solid dosage form. In some embodiments, diluent is about 77%(w/w) to about 82% (w/w) of the solid dosage form. In some embodiments,the diluent is about 78% (w/w) to about 80% (w/w) of the solid dosageform.

In some embodiments, at least a portion of the binder is in the granularcomponent. In some embodiments, the binder is selected from starches,gelatins, sugars, gums, waxes, water, alcohols, celluloses, andcombinations thereof. In some embodiments, the binder is selected fromacacia gum, tragacanth, corn starch, methyl cellulose, panwar gum,ghatti gum, mucilage of isapol husks, carboxymethylcellulose,methylcellulose, polyvinylpyrrolidone, sucrose, glucose, dextrose,molasses, lactose, and combinations thereof. In some embodiments, thebinder is hydroxypropyl cellulose. In some embodiments, the binder isabout 1% (w/w) to about 5% (w/w) of the solid dosage form. In someembodiments, binder is about 2% (w/w) to about 4% (w/w) of the soliddosage form. In some embodiments, the binder is about 2.5% (w/w) toabout 3.5% (w/w) of the solid dosage form.

In some embodiments, at least a portion of the coloring agent is in theextragranular component. In some embodiments, the coloring agent ispigment blend yellow. In some embodiments, the coloring agent is about0.30% (w/w) to about 0.60% (w/w) of the solid dosage form.

In some embodiments, at least a portion of the lubricant is in theextragranular component. In some embodiments, the lubricant is selectedfrom talc, magnesium stearate, calcium stearate, stearic acid, metallicstearate, hydrogenated vegetable oils, and polyethylene glycol, cornstarch, boric acids, sodium chloride, sodium lauryl sulphate. In someembodiments, the lubricant is magnesium stearate. In some embodiments,the lubricant is about 0.10% (w/w) to about 1% (w/w) of the solid dosageform. In some embodiments, the lubricant is about 0.50% (w/w) of thesolid dosage form.

In some embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is about 5% (w/w) to about 30% (w/w) of the solid dosage form.In some embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is about 10% (w/w) to about 20% (w/w) of the solid dosage form.In some embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is about 12% (w/w) to about 13% (w/w) of the solid dosage form.In some embodiments, the solid dosage form comprises about 10 mg of therofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the solid dosage form comprises about 10.5 mg of therofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the solid dosage form comprises about 11 mg of therofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the solid dosage form comprises about 11.5 mg of therofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the solid dosage form comprises about 12 mg of therofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the solid dosage form comprises about 12.5 mg of therofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the solid dosage form comprises about 17.5 mg of therofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the solid dosage form comprises about 20 mg of therofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the solid dosage form comprises about 21 mg of therofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the solid dosage form comprises about 22 mg of therofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the solid dosage form comprises about 22.5 mg of therofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the solid dosage form comprises about 25 mg of therofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the solid dosage form comprises about 50 mg of therofecoxib or pharmaceutically acceptable salt thereof.

In some embodiments, the rofecoxib is highly pure. In some embodiments,the highly pure rofecoxib comprises less than about 0.1% totalimpurities. In some embodiments, the highly pure rofecoxib comprisesless than about 0.075% total impurities. In some embodiments, the highlypure rofecoxib comprises less than about 0.050% total impurities. Insome embodiments, the highly pure rofecoxib comprises less than about0.025% total impurities. In some embodiments, the highly pure rofecoxibcomprises less than about 0.001% total impurities.

In some embodiments, the highly pure rofecoxib comprises less than about0.10%, 0.05%, 0.02%, or 0.01% of4-[4-(methylsulphonyl)phenyl]-3-phenyl-2,5-furandione. In someembodiments, the highly pure rofecoxib comprises less than about 0.10%,0.05%, 0.02%, or 0.01% of4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some embodiments,the highly pure rofecoxib comprises less than about 0.10%, 0.05%, 0.02%,or 0.01% of 4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In someembodiments, the highly pure rofecoxib comprises less than about 0.10%,0.05%, 0.02%, or 0.01% of4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone.

In some embodiments, the solid dosage form is suitable for oraladministration. In some embodiments, the solid dosage form is an oraltablet. In some embodiments, the oral tablet provides a dissolution rateof at least about 80% of the rofecoxib or pharmaceutically acceptablesalt thereof by about 15 minutes. In some embodiments, the oral tabletprovides a dissolution rate of at least about 85% of the rofecoxib orpharmaceutically acceptable salt thereof by about 15 minutes. In someembodiments, the oral tablet provides a dissolution rate of at leastabout 90% of the rofecoxib or pharmaceutically acceptable salt thereofby about 15 minutes. In some embodiments, the oral tablet provides adissolution rate of at least about 95% of the rofecoxib orpharmaceutically acceptable salt thereof by about 15 minutes. In someembodiments, the oral tablet provides a dissolution rate of at leastabout 100% of the rofecoxib or pharmaceutically acceptable salt thereofby about 15 minutes.

In some embodiments, the dissolution rate is measured in about 1% SDS ata paddle speed of about 50 rpm and at a temperature of about 37.0°C.±0.5° C. In some embodiments, the dissolution rate is measured inabout 1% SDS at a paddle speed of about 75 rpm and at a temperature ofabout 37.0° C.±0.5° C. In some embodiments, the dissolution rate ismeasured in about 1.5% SDS at a paddle speed of about 50 rpm and at atemperature of about 37.0° C.±0.5° C. In some embodiments, thedissolution rate is measured in about 1.5% SDS at a paddle speed ofabout 75 rpm and at a temperature of about 37.0° C.±0.5° C. In someembodiments, the dissolution rate is measured in about 2% SDS at apaddle speed of about 50 rpm and at a temperature of about 37.0° C.±0.5°C. In some embodiments, the dissolution rate is measured in about 2% SDSat a paddle speed of about 75 rpm and at a temperature of about 37.0°C.±0.5° C. In some embodiments, the dissolution rate is measured using aUSP Type II apparatus. In some embodiments, the dissolution rate ismeasured with a USP Type II apparatus using 900 mL of 2% SDS, a paddlespeed of 50 rpm, and a temperature of 37.0° C.±0.5°.

In some embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 35% of thegranules are less than about 75 μm. In some embodiments, the rofecoxibor pharmaceutically acceptable salt thereof is formulated into granulesand at least about 55% of the granules are less than about 150 μm. Insome embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 75% of thegranules are less than about 250 μm. In some embodiments, the rofecoxibor pharmaceutically acceptable salt thereof is formulated into granulesand at least about 85% of the granules are less than about 425 μm. Insome embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 90% of thegranules are less than about 1000 μm.

In some embodiments, a 17.5 mg solid dosage formulation of rofecoxibreaches a median time to Cmax plasma concentration in 4 hours or lessfollowing single administration of the formulation to human subjects. Insome embodiments, a 17.5 mg solid dosage formulation of rofecoxibreaches a median time to Cmax plasma concentration in 3 hours or lessfollowing administration. In some embodiments, a 17.5 mg solid dosageformulation of rofecoxib reaches a median time to Cmax plasmaconcentration in 2.5 hours or less following administration. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib reaches amedian time to Cmax plasma concentration in 2 hours or less followingadministration. In some embodiments, a 17.5 mg solid dosage formulationof rofecoxib has a mean Cmax plasma concentration of more than 100ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean Cmax plasma concentration of more than 150 ng/ml,167 ng/ml, or 190 ng/ml. In some embodiments, a 17.5 mg solid dosageformulation of rofecoxib has a mean Cmax plasma concentration of morethan 200 ng/ml. In some embodiments, a 17.5 mg solid dosage formulationof rofecoxib has a mean Cmax plasma concentration of more than 220ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean Cmax plasma concentration of more than 250 ng/ml.In some embodiments, a 17.5 mg solid dosage formulation of rofecoxib hasa mean Cmax plasma concentration of more than 280 ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 1750 h*ng/ml. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib has a mean AUC_(0-∞) of more than2000 h*ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean AUC_(0-∞) of more than 2500 h*ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 3000 h*ng/ml. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib has a mean AUC_(0-∞) of more than3100 h*ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean AUC_(0-∞) of more than 3500 h*ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 4000 h*ng/ml. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib has a mean AUC_(0-∞) of more than4500 h*ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib reaches a Cmax plasma concentration of least 167 ng/ml, 170ng/ml, 175 ng/ml, 180 ng/ml, or higher following single administrationof the formulation to a human subject. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib reaches an AUC_(0-∞) of at least2600 h*ng/ml, 2750 h*ng/ml, 2900 h*ng/ml, 3050 h*ng/ml, 3100 h*ng/ml,3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml or higherfollowing single administration of the formulation to a human subject.

In some embodiments, a 20 mg solid dosage formulation of rofecoxibreaches a median time to Cmax plasma concentration in 4 hours or lessfollowing single administration of the formulation to human subjects. Insome embodiments, a 20 mg solid dosage formulation of rofecoxib reachesa median time to Cmax plasma concentration in 3 hours or less followingadministration. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib reaches a median time to Cmax plasma concentration in 2.5hours or less following administration. In some embodiments, a 20 mgsolid dosage formulation of rofecoxib reaches a median time to Cmaxplasma concentration in 2 hours or less following administration. Insome embodiments, a 20 mg solid dosage formulation of rofecoxib has amean Cmax plasma concentration of more than 150 ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 191 ng/ml, 200 ng/ml, 215 ng/ml,or 225 ng/ml. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib has a mean Cmax plasma concentration of more than 250 ng/ml.In some embodiments, a 20 mg solid dosage formulation of rofecoxib has amean Cmax plasma concentration of more than 258 ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 300 ng/ml. In some embodiments, a20 mg solid dosage formulation of rofecoxib has a mean AUC_(0-∞) of morethan 2000 h*ng/ml. In some embodiments, a 20 mg solid dosage formulationof rofecoxib has a mean AUC_(0-∞) of more than 2500 h*ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 3000 h*ng/ml. In some embodiments, a 20 mg soliddosage formulation of rofecoxib has a mean AUC_(0-∞) of more than 3400h*ng/ml. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib has a mean AUC_(0-∞) of more than 3500 h*ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 4000 h*ng/ml. In some embodiments, a 20 mg soliddosage formulation of rofecoxib reaches a Cmax plasma concentration ofleast 190 ng/ml, 205 ng/ml, 220 ng/ml, 235 ng/ml, 250 ng/ml, or higherfollowing single administration of the formulation to a human subject.In some embodiments, a 20 mg solid dosage formulation of rofecoxibreaches an AUC_(0-∞) of at least 3000 h*ng/ml, 3200 h*ng/ml, 3350h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800 h*ng/ml, 3950 h*ng/ml, orhigher following single administration of the formulation to a humansubject. In some embodiments, the rofecoxib formulation achieves a meanCmax plasma concentration within 80% to 125% of 259 ng/ml and a meanAUC_(0-∞) within 80% to 125% of 3550 h*ng/ml. In some embodiments, therofecoxib formulation achieves a mean plasma AUC_(0-∞) of about2840-4438 h*ng/ml and a mean plasma Cmax of about 207-324 ng/mlfollowing oral administration of a single dose of the formulation to apopulation of healthy adults less than 65 years of age in a fastedstate. In some embodiments, the population of healthy adults are lessthan 60 years of age.

In some embodiments, a 25 mg solid dosage formulation of rofecoxibreaches a mean Cmax plasma concentration in less than 3 hours followingsingle administration of the formulation to human subjects. In someembodiments, a 25 mg solid dosage formulation of rofecoxib reaches amean Cmax plasma concentration in less than 2.5 hours followingadministration. In some embodiments, a 25 mg solid dosage formulation ofrofecoxib reaches a mean Cmax plasma concentration in less than 2 hoursfollowing administration. In some embodiments, a 25 mg solid dosageformulation of rofecoxib has a mean Cmax plasma concentration of morethan 240 ng/ml. In some embodiments, a 25 mg solid dosage formulation ofrofecoxib has a mean Cmax plasma concentration of more than 250 ng/ml.In some embodiments, a 25 mg solid dosage formulation of rofecoxib has amean Cmax plasma concentration of more than 300 ng/ml. In someembodiments, a 25 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 320 ng/ml. In some embodiments, a25 mg solid dosage formulation of rofecoxib has a mean AUC_(0-∞) of morethan 4250 h*ng/ml. In some embodiments, a 25 mg solid dosage formulationof rofecoxib has a mean AUC_(0-∞) of more than 4500 h*ng/ml. In someembodiments, a 25 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 4700 h*ng/ml. In some embodiments, a 25 mg soliddosage formulation of rofecoxib has a mean AUC_(0-∞) of more than 5000h*ng/ml. In some embodiments, a 25 mg solid dosage formulation ofrofecoxib reaches a mean Cmax plasma concentration of more than 240ng/ml in a median time of about 3 hours or less following administrationwith an AUC_(0-∞) of more than 4250 h*ng/ml.

In some embodiments, a 10 mg to 50 mg solid dosage formulation ofrofecoxib achieves a mean Cmax plasma concentration from 9.8 ng/ml to 16ng/ml for each 1 mg of rofecoxib in the formulation following singleadministration of the formulation to human subjects. In someembodiments, the solid dosage formulation achieves a mean Cmax plasmaconcentration from 10 ng/ml to 14 ng/ml for each 1 mg of rofecoxib inthe formulation. In some embodiments, the solid dosage formulationachieves a mean Cmax plasma concentration from 10 ng/ml to 13 ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, thesolid dosage formulation achieves a mean Cmax plasma concentration from80% to 125% of 12.8 ng/ml. In some embodiments, the solid dosageformulation reaches a mean AUC_(0-∞) of 170 h*ng/ml to 235 h*ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, thesolid dosage formulation reaches a mean AUC_(0-∞) of 170 h*ng/ml to 225h*ng/ml for each 1 mg of rofecoxib in the formulation. In someembodiments, the formulation achieves a mean AUC_(0-∞) of 177 h*ng/ml to225 h*ng/ml for each 1 mg of rofecoxib in the formulation. In someembodiments, the formulation achieves a mean AUC_(0-∞) of 180 h*ng/ml to225 h*ng/ml for each 1 mg of rofecoxib in the formulation. In someembodiments, the solid dosage formulation reaches a mean AUC_(0-∞) of190 h*ng/ml to 215 h*ng/ml for each 1 mg of rofecoxib in theformulation.

In certain aspects, the subject matter disclosed herein provides amethod for inhibiting COX-2 in a subject in need thereof, the methodcomprising administering to the subject a solid dosage formulationcomprising 17.5 mg of rofecoxib or a pharmaceutically acceptable saltthereof. In some embodiments, the formulation achieves a median time toCmax plasma concentration in 4 hours or less following singleadministration of the formulation to human subjects. In someembodiments, the formulation achieves a median time to Cmax plasmaconcentration in 3 hours or less following administration. In someembodiments, the formulation achieves a median time to Cmax plasmaconcentration in 2.5 hours or less following administration. In someembodiments, the formulation achieves a median time to Cmax plasmaconcentration in 2 hours or less following administration. In someembodiments, the formulation achieves a mean Cmax plasma concentrationof more than 100 ng/ml. In some embodiments, the formulation achieves amean Cmax plasma concentration of more than 150 ng/ml, 167 ng/ml, or 190ng/ml. In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 200 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 220ng/ml. In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 250 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 280ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞) ofmore than 1750 h*ng/ml. In some embodiments, the formulation achieves amean AUC_(0-∞) of more than 2000 h*ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 2500 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 3000h*ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞)of more than 3100 h*ng/ml. In some embodiments, the formulation achievesa mean AUC_(0-∞) of more than 3500 h*ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 4000 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 4500h*ng/ml. In some embodiments, the formulation reaches a Cmax plasmaconcentration of least 167 ng/ml, 170 ng/ml, 175 ng/ml, 180 ng/ml, orhigher following single administration of the formulation to a humansubject. In some embodiments, the formulation reaches an AUC_(0-∞) of atleast 2600 h*ng/ml, 2750 h*ng/ml, 2900 h*ng/ml, 3050 h*ng/ml, 3200h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml or higher followingsingle administration of the formulation to a human subject.

In certain aspects, the subject matter disclosed herein provides amethod for inhibiting COX-2 in a subject in need thereof, the methodcomprising administering to the subject a solid dosage formulationcomprising 20 mg of rofecoxib or a pharmaceutically acceptable saltthereof. In some embodiments, the formulation achieves a median time toCmax plasma concentration in 4 hours or less following singleadministration of the formulation to human subjects. In someembodiments, the formulation achieves a median time to Cmax plasmaconcentration in 3 hours or less following administration. In someembodiments, the formulation achieves a median time to Cmax plasmaconcentration in 2.5 hours or less following administration. In someembodiments, the formulation achieves a median time to Cmax plasmaconcentration in 2 hours or less following administration. In someembodiments, the formulation achieves a mean Cmax plasma concentrationof more than 150 ng/ml. In some embodiments, the formulation achieves amean Cmax plasma concentration of more than 191 ng/ml, 200 ng/ml, 215ng/ml, or 225 ng/ml. In some embodiments, the formulation achieves amean Cmax plasma concentration of more than 250 ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 258 ng/ml. In some embodiments,the formulation achieves a mean Cmax plasma concentration of more than300 ng/ml. In some embodiments, the formulation achieves a meanAUC_(0-∞) of more than 2000 h*ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 2500 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 3000h*ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞)of more than 3400 h*ng/ml. In some embodiments, the formulation achievesa mean AUC_(0-∞) of more than 3500 h*ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 4000 h*ng/ml. In someembodiments, the formulation reaches a Cmax plasma concentration ofleast 190 ng/ml, 205 ng/ml, 220 ng/ml, 235 ng/ml, 250 ng/ml, or higherfollowing single administration of the formulation to a human subject.In some embodiments, the formulation reaches an AUC_(0-∞) of at least3000 h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml,3800 h*ng/ml, 3950 h*ng/ml, or higher following single administration ofthe formulation to a human subject. In some embodiments, the rofecoxibformulation achieves a mean Cmax plasma concentration within 80% to 125%of 259 ng/ml and a mean AUC_(0-∞) within 80% to 125% of 3550 h*ng/ml. Insome embodiments, the rofecoxib formulation achieves a mean plasmaAUC_(0-∞) of about 2840-4438 h*ng/ml and a mean plasma Cmax of about207-324 ng/ml following oral administration of a single dose of theformulation to a population of healthy adults less than 65 years of agein a fasted state. In some embodiments, the population of healthy adultsare less than 60 years of age.

In certain aspects, the subject matter disclosed herein provides amethod for inhibiting COX-2 in a subject in need thereof, the methodcomprising administering to the subject a solid dosage formulationcomprising 25 mg of rofecoxib or a pharmaceutically acceptable saltthereof. In some embodiments, the formulation achieves a mean Cmaxplasma concentration in less than 3 hours following singleadministration of the formulation to human subjects. In someembodiments, the formulation achieves a mean Cmax plasma concentrationin less than 2.5 hours following administration. In some embodiments,the formulation achieves a mean Cmax plasma concentration in less than 2hours following administration. In some embodiments, the formulationachieves a mean Cmax plasma concentration of more than 240 ng/ml. Insome embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 250 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 300ng/ml. In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 320 ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 4250 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 4500h*ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞)of more than 4550 h*ng/ml. In some embodiments, the formulation achievesa mean AUC_(0-∞) of more than 4700 h*ng/ml. In some embodiments, theformulation achieves a Cmax plasma concentration of more than 240 ng/mlabout 3 hours following administration with an AUC_(0-∞) of more than4250 h*ng/ml.

In certain aspects, the subject matter disclosed herein provides amethod for inhibiting COX-2 in a subject in need thereof, the methodcomprising administering to the subject a solid dosage formulationcomprising 10 mg to 50 mg of rofecoxib or a pharmaceutically acceptablesalt thereof. In some embodiments, the formulation achieves a mean Cmaxplasma concentration from 9.8 ng/ml to 16 ng/ml for each 1 mg ofrofecoxib in the formulation following single administration of theformulation to human subjects. In some embodiments, the formulationachieves a mean Cmax plasma concentration from 10 ng/ml to 14 ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, theformulation achieves a mean Cmax plasma concentration from 10 ng/ml to13 ng/ml for each 1 mg of rofecoxib in the formulation. In someembodiments, the formulation achieves a mean Cmax plasma concentrationfrom 80% to 125% of 12.8 ng/ml. In some embodiments, the formulationreaches a mean AUC_(0-∞) of 170 h*ng/ml to 235 h*ng/ml for each 1 mg ofrofecoxib in the formulation. In some embodiments, the formulationreaches a mean AUC_(0-∞) of 177 h*ng/ml to 225 h*ng/ml for each 1 mg ofrofecoxib in the formulation. In some embodiments, the formulationreaches a mean AUC_(0-∞) of 190 h*ng/ml to 215 h*ng/ml for each 1 mg ofrofecoxib in the formulation.

A method for treating one or more conditions in a subject in needthereof, the method comprising administering to the subject apharmaceutically acceptable formulation comprising a granular componentand an extragranular component, wherein the granular component comprisesan intragranular component comprising rofecoxib or a pharmaceuticallyacceptable salt thereof and one or more disintegrants, and wherein theextragranular component comprises one or more disintegrants.

In some embodiments, the one or more disintegrants in the granularcomponent is selected from starches, clays, celluloses, algins, gums,cross-linked polymers, and combinations thereof. In some embodiments,the one or more disintegrants in the granular component is selected fromcroscarmellose, crospovidone, sodium starch glycolate, and combinationsthereof.

In some embodiments, the one or more disintegrants in the granularcomponent is croscarmellose sodium. In some embodiments, the one or moredisintegrants in the granular component is about 1% (w/w) to about 8%(w/w) of the formulation. In some embodiments, the one or moredisintegrants in the granular component is about 1% (w/w) to about 6%(w/w) of the formulation. In some embodiments, the one or moredisintegrants in the granular component is about 1% (w/w) to about 4%(w/w) of the formulation.

In some embodiments, the one or more disintegrants in the extragranularcomponent is selected from starches, clays, celluloses, algins, gums,cross-linked polymers, and combinations thereof. In some embodiments,the one or more disintegrants in the extragranular component is selectedfrom croscarmellose, crospovidone, sodium starch glycolate, andcombinations thereof. In some embodiments, the one or more disintegrantsin the extragranular component is croscarmellose sodium. In someembodiments, the disintegrant in the extragranular component is about 1%(w/w) to about 8% (w/w) of the formulation. In some embodiments, thedisintegrant in the extragranular component is about 1% (w/w) to about6% (w/w) of the formulation. In some embodiments, the disintegrant inthe extragranular component is about 1% (w/w) to about 4% (w/w) of theformulation.

In some embodiments, the disintegrant in the granular component and thedisintegrant in the extragranular component are together about 2% (w/w)to about 12% (w/w) of the formulation. In some embodiments, thedisintegrant in the granular component and the disintegrant in theextragranular component are together about 2% (w/w) to about 10% (w/w)of the formulation. In some embodiments, the disintegrant in thegranular component and the disintegrant in the extragranular componentare together about 2% (w/w) to about 8% (w/w) of the formulation.

In some embodiments, the ratio of granular disintegrant to extragranulardisintegrant is about 40% (w/w) to about 60% (w/w). In some embodiments,the ratio of granular disintegrant to extragranular disintegrant isabout 45% (w/w) to about 55% (w/w). In some embodiments, the ratio ofgranular disintegrant to extragranular disintegrant is about 50% (w/w)to about 50% (w/w). In some embodiments, the ratio of granulardisintegrant to extragranular disintegrant is about 55% (w/w) to about45% (w/w). In some embodiments, the ratio of granular disintegrant toextragranular disintegrant is about 60% (w/w) to about 40% (w/w).

In some embodiments, the pharmaceutically acceptable formulation furthercomprising one or more of a diluent, a binder, a coloring agent, and alubricant. In some embodiments, at least a portion of the diluent is inthe granular component. In some embodiments, the diluent is selectedfrom dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin,mannitol, sodium chloride, dry starch, powdered sugar, sorbitol,sucrose, inositol, and combinations thereof. In some embodiments, thediluent is selected from lactose, cellulose, or a combination thereof.In some embodiments, the diluent is selected from lactose monohydrate,microcrystalline cellulose, or a combination thereof.

In some embodiments, the lactose monohydrate is about 35% (w/w) to about45% (w/w) of the formulation. In some embodiments, the lactosemonohydrate is about 37% (w/w) to about 42% (w/w) of the formulation. Insome embodiments, the lactose monohydrate is about 39% (w/w) to about40% (w/w) of the formulation.

In some embodiments, the microcrystalline cellulose is about 35% (w/w)to about 45% (w/w) of the formulation. In some embodiments, themicrocrystalline cellulose is about 37% (w/w) to about 42% (w/w) of theformulation. In some embodiments, the microcrystalline cellulose isabout 39% (w/w) to about 40% (w/w) of the formulation.

In some embodiments, the diluent is about 75% (w/w) to about 85% (w/w)of the formulation. In some embodiments, diluent is about 77% (w/w) toabout 82% (w/w) of the formulation. In some embodiments, the diluent isabout 78% (w/w) to about 80% (w/w) of the formulation.

In some embodiments, at least a portion of the binder is in the granularcomponent. In some embodiments, the binder is selected from starches,gelatins, sugars, gums, waxes, water, alcohols, celluloses, andcombinations thereof. In some embodiments, the binder is selected fromacacia gum, tragacanth, corn starch, methyl cellulose, panwar gum,ghatti gum, mucilage of isapol husks, carboxymethylcellulose,methylcellulose, polyvinylpyrrolidone, sucrose, glucose, dextrose,molasses, lactose, and combinations thereof. In some embodiments, thebinder is hydroxypropyl cellulose. In some embodiments, the binder isabout 1% (w/w) to about 5% (w/w) of the formulation. In someembodiments, binder is about 2% (w/w) to about 4% (w/w) of theformulation. In some embodiments, the binder is about 2.5% (w/w) toabout 3.5% (w/w) of the formulation.

In some embodiments, at least a portion of the coloring agent is in theextragranular component. In some embodiments, the coloring agent ispigment blend yellow. In some embodiments, the coloring agent is about0.30% (w/w) to about 0.60% (w/w) of the formulation.

In some embodiments, at least a portion of the lubricant is in theextragranular component. In some embodiments, the lubricant is selectedfrom talc, magnesium stearate, calcium stearate, stearic acid, metallicstearate, hydrogenated vegetable oils, and polyethylene glycol, cornstarch, boric acids, sodium chloride, sodium lauryl sulphate. In someembodiments, the lubricant is magnesium stearate. In some embodiments,the lubricant is about 0.10% (w/w) to about 1% (w/w) of the formulation.In some embodiments, the lubricant is about 0.50% (w/w) of theformulation.

In some embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is about 5% (w/w) to about 30% (w/w) of the formulation. In someembodiments, the rofecoxib or pharmaceutically acceptable salt thereofis about 10% (w/w) to about 20% (w/w) of the formulation. In someembodiments, the rofecoxib or pharmaceutically acceptable salt thereofis about 12% (w/w) to about 13% (w/w) of the formulation. In someembodiments, the formulation comprises about 10 mg of the rofecoxib orpharmaceutically acceptable salt thereof. In some embodiments, theformulation comprises about 10.5 mg of the rofecoxib or pharmaceuticallyacceptable salt thereof. In some embodiments, the formulation comprisesabout 11 mg of the rofecoxib or pharmaceutically acceptable saltthereof. In some embodiments, the formulation comprises about 11.5 mg ofthe rofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the formulation comprises about 12 mg of the rofecoxib orpharmaceutically acceptable salt thereof. In some embodiments, theformulation comprises about 12.5 mg of the rofecoxib or pharmaceuticallyacceptable salt thereof. In some embodiments, the formulation comprisesabout 17.5 mg of the rofecoxib or pharmaceutically acceptable saltthereof. In some embodiments, the formulation comprises about 20 mg ofthe rofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the formulation comprises about 21 mg of the rofecoxib orpharmaceutically acceptable salt thereof. In some embodiments, theformulation comprises about 22 mg of the rofecoxib or pharmaceuticallyacceptable salt thereof. In some embodiments, the formulation comprisesabout 22.5 mg of the rofecoxib or pharmaceutically acceptable saltthereof. In some embodiments, the formulation comprises about 25 mg ofthe rofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the formulation comprises about 50 mg of the rofecoxib orpharmaceutically acceptable salt thereof.

In some embodiments, the rofecoxib is highly pure. In some embodiments,the highly pure rofecoxib comprises less than about 0.1% totalimpurities. In some embodiments, the highly pure rofecoxib comprisesless than about 0.075% total impurities. In some embodiments, the highlypure rofecoxib comprises less than about 0.050% total impurities. Insome embodiments, the highly pure rofecoxib comprises less than about0.025% total impurities. In some embodiments, the highly pure rofecoxibcomprises less than about 0.001% total impurities.

In some embodiments, the highly pure rofecoxib comprises less than about0.10%, 0.05%, 0.02%, or 0.01% of4-[4-(methylsulphonyl)phenyl]-3-phenyl-2,5-furandione. In someembodiments, the highly pure rofecoxib comprises less than about 0.10%,0.05%, 0.02%, or 0.01% of4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some embodiments,the highly pure rofecoxib comprises less than about 0.10%, 0.05%, 0.02%,or 0.01% of 4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In someembodiments, the highly pure rofecoxib comprises less than about 0.10%,0.05%, 0.02%, or 0.01% of4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone.

In some embodiments, the formulation is suitable for oraladministration. In some embodiments, the formulation is a solid dosageform. In some embodiments, the solid dosage form is an oral tablet. Insome embodiments, the oral tablet provides a dissolution rate of atleast about 80% of the rofecoxib or pharmaceutically acceptable saltthereof by about 15 minutes. In some embodiments, the oral tabletprovides a dissolution rate of at least about 85% of the rofecoxib orpharmaceutically acceptable salt thereof by about 15 minutes. In someembodiments, the oral tablet provides a dissolution rate of at leastabout 90% of the rofecoxib or pharmaceutically acceptable salt thereofby about 15 minutes. In some embodiments, the oral tablet provides adissolution rate of at least about 95% of the rofecoxib orpharmaceutically acceptable salt thereof by about 15 minutes. In someembodiments, the oral tablet provides a dissolution rate of at leastabout 100% of the rofecoxib or pharmaceutically acceptable salt thereofby about 15 minutes.

In some embodiments, the dissolution rate is measured in about 1% SDS ata paddle speed of about 50 rpm and at a temperature of about 37.0°C.±0.5° C. In some embodiments, the dissolution rate is measured inabout 1% SDS at a paddle speed of about 75 rpm and at a temperature ofabout 37.0° C.±0.5° C. In some embodiments, the dissolution rate ismeasured in about 1.5% SDS at a paddle speed of about 50 rpm and at atemperature of about 37.0° C.±0.5° C. In some embodiments, thedissolution rate is measured in about 1.5% SDS at a paddle speed ofabout 75 rpm and at a temperature of about 37.0° C.±0.5° C. In someembodiments, the dissolution rate is measured in about 2% SDS at apaddle speed of about 50 rpm and at a temperature of about 37.0° C.±0.5°C. In some embodiments, the dissolution rate is measured in about 2% SDSat a paddle speed of about 75 rpm and at a temperature of about 37.0°C.±0.5° C. In some embodiments, the dissolution rate is measured using aUSP Type II apparatus. In some embodiments, the dissolution rate ismeasured with a USP Type II apparatus using 900 mL of 2% SDS, a paddlespeed of 50 rpm, and a temperature of 37.0° C.±0.5°.

In some embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 35% of thegranules are less than about 75 μm. In some embodiments, the rofecoxibor pharmaceutically acceptable salt thereof is formulated into granulesand at least about 55% of the granules are less than about 150 μm. Insome embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 75% of thegranules are less than about 250 μm. In some embodiments, the rofecoxibor pharmaceutically acceptable salt thereof is formulated into granulesand at least about 85% of the granules are less than about 425 μm. Insome embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 90% of thegranules are less than about 1000 μm.

In some embodiments, a 17.5 mg solid dosage formulation of rofecoxibreaches a median time to Cmax plasma concentration in 4 hours or lessfollowing single administration of the formulation to human subjects. Insome embodiments, a 17.5 mg solid dosage formulation of rofecoxibreaches a median time to Cmax plasma concentration in 3 hours or lessfollowing administration. In some embodiments, a 17.5 mg solid dosageformulation of rofecoxib reaches a median time to Cmax plasmaconcentration in 2.5 hours or less following administration. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib reaches amedian time to Cmax plasma concentration in 2 hours or less followingadministration. In some embodiments, a 17.5 mg solid dosage formulationof rofecoxib has a mean Cmax plasma concentration of more than 100ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean Cmax plasma concentration of more than 150 ng/ml,167 ng/ml, or 190 ng/ml. In some embodiments, a 17.5 mg solid dosageformulation of rofecoxib has a mean Cmax plasma concentration of morethan 200 ng/ml. In some embodiments, a 17.5 mg solid dosage formulationof rofecoxib has a mean Cmax plasma concentration of more than 220ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean Cmax plasma concentration of more than 250 ng/ml.In some embodiments, a 17.5 mg solid dosage formulation of rofecoxib hasa mean Cmax plasma concentration of more than 280 ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 1750 h*ng/ml. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib has a mean AUC_(0-∞) of more than2000 h*ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean AUC_(0-∞) of more than 2500 h*ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 3000 h*ng/ml. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib has a mean AUC_(0-∞) of more than3100 h*ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean AUC_(0-∞) of more than 3500 h*ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 4000 h*ng/ml. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib has a mean AUC_(0-∞) of more than4500 h*ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib reaches a Cmax plasma concentration of least 167 ng/ml, 170ng/ml, 175 ng/ml, 180 ng/ml, or higher following single administrationof the formulation to a human subject. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib reaches an AUC_(0-∞) of at least2600 h*ng/ml, 2750 h*ng/ml, 2900 h*ng/ml, 3050 h*ng/ml, 3100 h*ng/ml,3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml or higherfollowing single administration of the formulation to a human subject.

In some embodiments, a 20 mg solid dosage formulation of rofecoxibreaches a median time to Cmax plasma concentration in 4 hours or lessfollowing single administration of the formulation to human subjects. Insome embodiments, a 20 mg solid dosage formulation of rofecoxib reachesa median time to Cmax plasma concentration in 3 hours or less followingadministration. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib reaches a median time to Cmax plasma concentration in 2.5hours or less following administration. In some embodiments, a 20 mgsolid dosage formulation of rofecoxib reaches a median time to Cmaxplasma concentration in 2 hours or less following administration. Insome embodiments, a 20 mg solid dosage formulation of rofecoxib has amean Cmax plasma concentration of more than 150 ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 191 ng/ml, 200 ng/ml, 215 ng/ml,or 225 ng/ml. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib has a mean Cmax plasma concentration of more than 250 ng/ml.In some embodiments, a 20 mg solid dosage formulation of rofecoxib has amean Cmax plasma concentration of more than 258 ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 300 ng/ml. In some embodiments, a20 mg solid dosage formulation of rofecoxib has a mean AUC_(0-∞) of morethan 2000 h*ng/ml. In some embodiments, a 20 mg solid dosage formulationof rofecoxib has a mean AUC_(0-∞) of more than 2500 h*ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 3000 h*ng/ml. In some embodiments, a 20 mg soliddosage formulation of rofecoxib has a mean AUC_(0-∞) of more than 3400h*ng/ml. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib has a mean AUC_(0-∞) of more than 3500 h*ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 4000 h*ng/ml. In some embodiments, a 20 mg soliddosage formulation of rofecoxib reaches a Cmax plasma concentration ofleast 190 ng/ml, 205 ng/ml, 220 ng/ml, 235 ng/ml, 250 ng/ml, or higherfollowing single administration of the formulation to a human subject.In some embodiments, a 20 mg solid dosage formulation of rofecoxibreaches an AUC_(0-∞) of at least 3000 h*ng/ml, 3200 h*ng/ml, 3350h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800 h*ng/ml, 3950 h*ng/ml, orhigher following single administration of the formulation to a humansubject. In some embodiments, the rofecoxib formulation achieves a meanCmax plasma concentration within 80% to 125% of 259 ng/ml and a meanAUC_(0-∞) within 80% to 125% of 3550 h*ng/ml. In some embodiments, therofecoxib formulation achieves a mean plasma AUC_(0-∞) of about2840-4438 h*ng/ml and a mean plasma Cmax of about 207-324 ng/mlfollowing oral administration of a single dose of the formulation to apopulation of healthy adults less than 65 years of age in a fastedstate. In some embodiments, the population of healthy adults are lessthan 60 years of age.

In some embodiments, a 25 mg solid dosage formulation of rofecoxibreaches a mean Cmax plasma concentration in less than 3 hours followingsingle administration of the formulation to human subjects. In someembodiments, a 25 mg solid dosage formulation of rofecoxib reaches amean Cmax plasma concentration in less than 2.5 hours followingadministration. In some embodiments, a 25 mg solid dosage formulation ofrofecoxib reaches a mean Cmax plasma concentration in less than 2 hoursfollowing administration. In some embodiments, a 25 mg solid dosageformulation of rofecoxib has a mean Cmax plasma concentration of morethan 240 ng/ml. In some embodiments, a 25 mg solid dosage formulation ofrofecoxib has a mean Cmax plasma concentration of more than 250 ng/ml.In some embodiments, a 25 mg solid dosage formulation of rofecoxib has amean Cmax plasma concentration of more than 300 ng/ml. In someembodiments, a 25 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 320 ng/ml. In some embodiments, a25 mg solid dosage formulation of rofecoxib has a mean AUC_(0-∞) of morethan 4250 h*ng/ml. In some embodiments, a 25 mg solid dosage formulationof rofecoxib has a mean AUC_(0-∞) of more than 4500 h*ng/ml. In someembodiments, a 25 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 4550 h*ng/ml. In some embodiments, a 25 mg soliddosage formulation of rofecoxib has a mean AUC_(0-∞) of more than 4700h*ng/ml. In some embodiments, a 25 mg solid dosage formulation ofrofecoxib reaches a Cmax plasma concentration of more than 240 ng/ml ina median time of about 3 hours or less following administration with anAUC_(0-∞) of more than 4250 h*ng/ml.

In some embodiments, a 10 mg to 50 mg solid dosage formulation ofrofecoxib achieves a mean Cmax plasma concentration from 9.8 ng/ml to 16ng/ml for each 1 mg of rofecoxib in the formulation following singleadministration of the formulation to human subjects. In someembodiments, a 10 mg to 50 mg solid dosage formulation achieves a meanCmax plasma concentration from 10 ng/ml to 14 ng/ml for each 1 mg ofrofecoxib in the formulation. In some embodiments, a 10 mg to 50 mgsolid dosage formulation achieves a mean Cmax plasma concentration from10 ng/ml to 13 ng/ml for each 1 mg of rofecoxib in the formulation. Insome embodiments, a 10 mg to 50 mg solid dosage formulation achieves amean Cmax plasma concentration from 80% to 125% of 12.8 ng/ml. In someembodiments, a 10 mg to 50 mg solid dosage formulation reaches a meanAUC_(0-∞) of 170 h*ng/ml to 235 h*ng/ml for each 1 mg of rofecoxib inthe formulation. In some embodiments, a 10 mg to 50 mg solid dosageformulation reaches a mean AUC_(0-∞) of 170 h*ng/ml to 225 h*ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, theformulation achieves a mean AUC_(0-∞) of 177 h*ng/ml to 225 h*ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, theformulation achieves a mean AUC_(0-∞) of 180 h*ng/ml to 225 h*ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, a 10 mgto 50 mg solid dosage formulation reaches a mean AUC_(0-∞) of 190h*ng/ml to 215 h*ng/ml for each 1 mg of rofecoxib in the formulation.

In certain aspects, the subject matter disclosed herein provides amethod for treating one or more conditions in a subject in need thereof,the method comprising administering to the subject a pharmaceuticallyacceptable formulation comprising a granular component and anextragranular component, wherein the granular component comprises anintragranular component comprising a 17.5 mg of rofecoxib or apharmaceutically acceptable salt thereof. In some embodiments, theformulation achieves a median time to Cmax plasma concentration in 4hours or less following single administration of the formulation tohuman subjects. In some embodiments, the formulation achieves a mediantime to Cmax plasma concentration in 3 hours or less followingadministration. In some embodiments, the formulation achieves a meanCmax plasma concentration in less than 2.5 hours followingadministration. In some embodiments, the formulation achieves a mediantime to Cmax plasma concentration in 2 hours or less followingadministration. In some embodiments, the formulation achieves a meanCmax plasma concentration of more than 100 ng/ml. In some embodiments,the formulation achieves a mean Cmax plasma concentration of more than150 ng/ml, 167 ng/ml, or 190 ng/ml. In some embodiments, the formulationachieves a mean Cmax plasma concentration of more than 200 ng/ml. Insome embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 250 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 280ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞) ofmore than 1750 h*ng/ml. In some embodiments, the formulation achieves amean AUC_(0-∞) of more than 2000 h*ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 2500 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 3000h*ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞)of more than 3100 h*ng/ml. In some embodiments, the formulation achievesa mean AUC_(0-∞) of more than 3500 h*ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 4000 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 4500h*ng/ml.

In certain aspects, the subject matter disclosed herein provides amethod for treating one or more conditions in a subject in need thereof,the method comprising administering to the subject a pharmaceuticallyacceptable formulation comprising a granular component and anextragranular component, wherein the granular component comprises anintragranular component comprising 20 mg of rofecoxib or apharmaceutically acceptable salt thereof. In some embodiments, theformulation achieves a median time to Cmax plasma concentration in 4hours or less following single administration of the formulation tohuman subjects. In some embodiments, the formulation achieves a mediantime to Cmax plasma concentration in 3 hours or less followingadministration. In some embodiments, the formulation achieves a mediantime to Cmax plasma concentration in 2.5 hours or less followingadministration. In some embodiments, the formulation achieves a mediantime to Cmax plasma concentration in 2 hours or less followingadministration. In some embodiments, the formulation achieves a meanCmax plasma concentration of more than 150 ng/ml. In some embodiments,the formulation achieves a mean Cmax plasma concentration of more than191 ng/ml, 200 ng/ml, 215 ng/ml, or 225 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 250ng/ml. In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 258 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 300ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞) ofmore than 2000 h*ng/ml. In some embodiments, the formulation achieves amean AUC_(0-∞) of more than 2500 h*ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 3000 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 3400h*ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞)of more than 3500 h*ng/ml. In some embodiments, the formulation achievesa mean AUC_(0-∞) of more than 4000 h*ng/ml. In some embodiments, theformulation reaches a Cmax plasma concentration of least 190 ng/ml, 205ng/ml, 220 ng/ml, 235 ng/ml, 250 ng/ml, or higher following singleadministration of the formulation to a human subject. In someembodiments, the formulation reaches an AUC_(0-∞) of at least 3000h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800h*ng/ml, 3950 h*ng/ml, or higher following single administration of theformulation to a human subject. In some embodiments, the rofecoxibformulation achieves a mean Cmax plasma concentration within 80% to 125%of 259 ng/ml and a mean AUC_(0-∞) within 80% to 125% of 3550 h*ng/ml. Insome embodiments, the rofecoxib formulation achieves a mean plasmaAUC_(0-∞) of about 2840-4438 h*ng/ml and a mean plasma Cmax of about207-324 ng/ml following oral administration of a single dose of theformulation to a population of healthy adults less than 65 years of agein a fasted state. In some embodiments, the population of healthy adultsare less than 60 years of age.

In certain aspects, the subject matter disclosed herein provides amethod for treating one or more conditions in a subject in need thereof,the method comprising administering to the subject a pharmaceuticallyacceptable formulation comprising a granular component and anextragranular component, wherein the granular component comprises anintragranular component comprising 25 mg of rofecoxib or apharmaceutically acceptable salt thereof. In some embodiments, theformulation achieves a mean Cmax plasma concentration in less than 3hours following single administration of the formulation to humansubjects. In some embodiments, the formulation achieves a mean Cmaxplasma concentration in less than 2.5 hours following administration. Insome embodiments, the formulation achieves a mean Cmax plasmaconcentration in less than 2 hours following administration. In someembodiments, the formulation achieves a mean Cmax plasma concentrationof more than 240 ng/ml. In some embodiments, the formulation achieves amean Cmax plasma concentration of more than 250 ng/ml. In someembodiments, the formulation achieves a mean Cmax plasma concentrationof more than 300 ng/ml. In some embodiments, the formulation achieves amean Cmax plasma concentration of more than 350 ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 4250h*ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞)of more than 4500 h*ng/ml. In some embodiments, the formulation achievesa mean AUC_(0-∞) of more than 4550 h*ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 4700 h*ng/ml. In someembodiments, the formulation achieves a Cmax plasma concentration ofmore than 240 ng/ml in about 3 hours following administration with anAUC_(0-∞) of more than 4250 h*ng/ml.

In certain aspects, the subject matter disclosed herein provides amethod for treating one or more conditions in a subject in need thereof,the method comprising administering to the subject a pharmaceuticallyacceptable formulation comprising a granular component and anextragranular component, wherein the granular component comprises anintragranular component comprising 10 mg to 50 mg of rofecoxib or apharmaceutically acceptable salt thereof. In some embodiments, theformulation achieves a mean Cmax plasma concentration from 9.8 ng/ml to16 ng/ml for each 1 mg of rofecoxib in the formulation following singleadministration of the formulation to human subjects. In someembodiments, the formulation achieves a mean Cmax plasma concentrationfrom 10 ng/ml to 14 ng/ml for each 1 mg of rofecoxib in the formulation.In some embodiments, the formulation achieves a mean Cmax plasmaconcentration from 10 ng/ml to 13 ng/ml for each 1 mg of rofecoxib inthe formulation. In some embodiments, the formulation achieves a meanCmax plasma concentration from 80% to 125% of 12.8 ng/ml. In someembodiments, the formulation reaches a mean AUC_(0-∞) of 170 h*ng/ml to235 h*ng/ml for each 1 mg of rofecoxib in the formulation. In someembodiments, the formulation reaches a mean AUC_(0-∞) of 170 h*ng/ml to225 h*ng/ml for each 1 mg of rofecoxib in the formulation. In someembodiments, the formulation achieves a mean AUC_(0-∞) of 177 h*ng/ml to225 h*ng/ml for each 1 mg of rofecoxib in the formulation. In someembodiments, the formulation achieves a mean AUC_(0-∞) of 180 h*ng/ml to225 h*ng/ml for each 1 mg of rofecoxib in the formulation. In someembodiments, the formulation reaches a mean AUC_(0-∞) of 190 h*ng/ml to215 h*ng/ml for each 1 mg of rofecoxib in the formulation.

A method for treating one or more conditions in a subject in needthereof, the method comprising administering to the subject a soliddosage form comprising a granular component and an extragranularcomponent, wherein the granular component comprises an intragranularcomponent comprising rofecoxib or a pharmaceutically acceptable saltthereof and one or more disintegrants, and wherein the extragranularcomponent comprises one or more disintegrants.

In some embodiments, the one or more disintegrants in the granularcomponent is selected from starches, clays, celluloses, algins, gums,cross-linked polymers, and combinations thereof. In some embodiments,the one or more disintegrants in the granular component is selected fromcroscarmellose, crospovidone, sodium starch glycolate, and combinationsthereof.

In some embodiments, the one or more disintegrants in the granularcomponent is croscarmellose sodium. In some embodiments, the one or moredisintegrants in the granular component is about 1% (w/w) to about 8%(w/w) of the solid dosage form. In some embodiments, the one or moredisintegrants in the granular component is about 1% (w/w) to about 6%(w/w) of the solid dosage form. In some embodiments, the one or moredisintegrants in the granular component is about 1% (w/w) to about 4%(w/w) of the solid dosage form.

In some embodiments, the one or more disintegrants in the extragranularcomponent is selected from starches, clays, celluloses, algins, gums,cross-linked polymers, and combinations thereof. In some embodiments,the one or more disintegrants in the extragranular component is selectedfrom croscarmellose, crospovidone, sodium starch glycolate, andcombinations thereof. In some embodiments, the one or more disintegrantsin the extragranular component is croscarmellose sodium. In someembodiments, the disintegrant in the extragranular component is about 1%(w/w) to about 8% (w/w) of the solid dosage form. In some embodiments,the disintegrant in the extragranular component is about 1% (w/w) toabout 6% (w/w) of the solid dosage form. In some embodiments, thedisintegrant in the extragranular component is about 1% (w/w) to about4% (w/w) of the solid dosage form.

In some embodiments, the disintegrant in the granular component and thedisintegrant in the extragranular component are together about 2% (w/w)to about 12% (w/w) of the solid dosage form. In some embodiments, thedisintegrant in the granular component and the disintegrant in theextragranular component are together about 2% (w/w) to about 10% (w/w)of the solid dosage form. In some embodiments, the disintegrant in thegranular component and the disintegrant in the extragranular componentare together about 2% (w/w) to about 8% (w/w) of the solid dosage form.

In some embodiments, the ratio of granular disintegrant to extragranulardisintegrant is about 40% (w/w) to about 60% (w/w). In some embodiments,the ratio of granular disintegrant to extragranular disintegrant isabout 45% (w/w) to about 55% (w/w). In some embodiments, the ratio ofgranular disintegrant to extragranular disintegrant is about 50% (w/w)to about 50% (w/w). In some embodiments the ratio of granulardisintegrant to extragranular disintegrant is about 55% (w/w) to about45% (w/w). In some embodiments the ratio of granular disintegrant toextragranular disintegrant is about 60% (w/w) to about 40% (w/w).

In some embodiments, the solid dosage form further comprises one or moreof a diluent, a binder, a coloring agent, and a lubricant. In someembodiments, at least a portion of the diluent is in the granularcomponent. In some embodiments, the diluent is selected from dicalciumphosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodiumchloride, dry starch, powdered sugar, sorbitol, sucrose, inositol, andcombinations thereof. In some embodiments, the diluent is selected fromlactose, cellulose, or a combination thereof. In some embodiments, thediluent is selected from lactose monohydrate, microcrystallinecellulose, or a combination thereof.

In some embodiments, the lactose monohydrate is about 35% (w/w) to about45% (w/w) of the solid dosage form. In some embodiments, the lactosemonohydrate is about 37% (w/w) to about 42% (w/w) of the solid dosageform. In some embodiments, the lactose monohydrate is about 39% (w/w) toabout 40% (w/w) of the solid dosage form.

In some embodiments, the microcrystalline cellulose is about 35% (w/w)to about 45% (w/w) of the solid dosage form. In some embodiments, themicrocrystalline cellulose is about 37% (w/w) to about 42% (w/w) of thesolid dosage form. In some embodiments, the microcrystalline celluloseis about 39% (w/w) to about 40% (w/w) of the solid dosage form.

In some embodiments, the diluent is about 75% (w/w) to about 85% (w/w)of the solid dosage form. In some embodiments, diluent is about 77%(w/w) to about 82% (w/w) of the solid dosage form. In some embodiments,the diluent is about 78% (w/w) to about 80% (w/w) of the solid dosageform.

In some embodiments, at least a portion of the binder is in the granularcomponent. In some embodiments, the binder is selected from starches,gelatins, sugars, gums, waxes, water, alcohols, celluloses, andcombinations thereof. In some embodiments, the binder is selected fromacacia gum, tragacanth, corn starch, methyl cellulose, panwar gum,ghatti gum, mucilage of isapol husks, carboxymethylcellulose,methylcellulose, polyvinylpyrrolidone, sucrose, glucose, dextrose,molasses, lactose, and combinations thereof. In some embodiments, thebinder is hydroxypropyl cellulose. In some embodiments, the binder isabout 1% (w/w) to about 5% (w/w) of the solid dosage form. In someembodiments, binder is about 2% (w/w) to about 4% (w/w) of the soliddosage form. In some embodiments, the binder is about 2.5% (w/w) toabout 3.5% (w/w) of the solid dosage form.

In some embodiments, at least a portion of the coloring agent is in theextragranular component. In some embodiments, the coloring agent ispigment blend yellow. In some embodiments, the coloring agent is about0.30% (w/w) to about 0.60% (w/w) of the solid dosage form.

In some embodiments, at least a portion of the lubricant is in theextragranular component. In some embodiments, the lubricant is selectedfrom talc, magnesium stearate, calcium stearate, stearic acid, metallicstearate, hydrogenated vegetable oils, and polyethylene glycol, cornstarch, boric acids, sodium chloride, sodium lauryl sulphate. In someembodiments, the lubricant is magnesium stearate. In some embodiments,the lubricant is about 0.10% (w/w) to about 1% (w/w) of the solid dosageform. In some embodiments, the lubricant is about 0.50% (w/w) of thesolid dosage form.

In some embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is about 5% (w/w) to about 30% (w/w) of the solid dosage form.In some embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is about 10% (w/w) to about 20% (w/w) of the solid dosage form.In some embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is about 12% (w/w) to about 13% (w/w) of the solid dosage form.In some embodiments, the solid dosage form comprises about 10 mg of therofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the solid dosage form comprises about 10.5 mg of therofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the solid dosage form comprises about 11 mg of therofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the solid dosage form comprises about 11.5 mg of therofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the solid dosage form comprises about 12 mg of therofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the solid dosage form comprises about 12.5 mg of therofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the solid dosage form comprises about 20 mg of therofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the solid dosage form comprises about 21 mg of therofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the solid dosage form comprises about 22 mg of therofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the solid dosage form comprises about 22.5 mg of therofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the solid dosage form comprises about 25 mg of therofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the solid dosage form comprises about 50 mg of therofecoxib or pharmaceutically acceptable salt thereof.

In some embodiments, the rofecoxib is highly pure. In some embodiments,the highly pure rofecoxib comprises less than about 0.1% totalimpurities. In some embodiments, the highly pure rofecoxib comprisesless than about 0.075% total impurities. In some embodiments, the highlypure rofecoxib comprises less than about 0.050% total impurities. Insome embodiments, the highly pure rofecoxib comprises less than about0.025% total impurities. In some embodiments, the highly pure rofecoxibcomprises less than about 0.001% total impurities.

In some embodiments, the highly pure rofecoxib comprises less than about0.10%, 0.05%, 0.02%, or 0.01% of4-[4-(methylsulphonyl)phenyl]-3-phenyl-2,5-furandione. In someembodiments, the highly pure rofecoxib comprises less than about 0.10%,0.05%, 0.02%, or 0.01% of4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some embodiments,the highly pure rofecoxib comprises less than about 0.10%, 0.05%, 0.02%,or 0.01% of 4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In someembodiments, the highly pure rofecoxib comprises less than about 0.10%,0.05%, 0.02%, or 0.01% of4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone.

In some embodiments, the solid dosage form is suitable for oraladministration. In some embodiments, the solid dosage form is an oraltablet. In some embodiments, the oral tablet provides a dissolution rateof at least about 80% of the rofecoxib or pharmaceutically acceptablesalt thereof by about 15 minutes. In some embodiments, the oral tabletprovides a dissolution rate of at least about 85% of the rofecoxib orpharmaceutically acceptable salt thereof by about 15 minutes. In someembodiments, the oral tablet provides a dissolution rate of at leastabout 90% of the rofecoxib or pharmaceutically acceptable salt thereofby about 15 minutes. In some embodiments, the oral tablet provides adissolution rate of at least about 95% of the rofecoxib orpharmaceutically acceptable salt thereof by about 15 minutes. In someembodiments, the oral tablet provides a dissolution rate of at leastabout 100% of the rofecoxib or pharmaceutically acceptable salt thereofby about 15 minutes.

In some embodiments, the dissolution rate is measured in about 1% SDS ata paddle speed of about 50 rpm and at a temperature of about 37.0°C.±0.5° C. In some embodiments, the dissolution rate is measured inabout 1% SDS at a paddle speed of about 75 rpm and at a temperature ofabout 37.0° C.±0.5° C. In some embodiments, the dissolution rate ismeasured in about 1.5% SDS at a paddle speed of about 50 rpm and at atemperature of about 37.0° C.±0.5° C. In some embodiments, thedissolution rate is measured in about 1.5% SDS at a paddle speed ofabout 75 rpm and at a temperature of about 37.0° C.±0.5° C. In someembodiments, the dissolution rate is measured in about 2% SDS at apaddle speed of about 50 rpm and at a temperature of about 37.0° C.±0.5°C. In some embodiments, the dissolution rate is measured in about 2% SDSat a paddle speed of about 75 rpm and at a temperature of about 37.0°C.±0.5° C. In some embodiments, the dissolution rate is measured using aUSP Type II apparatus. In some embodiments, the dissolution rate ismeasured with a USP Type II apparatus using 900 mL of 2% SDS, a paddlespeed of 50 rpm, and a temperature of 37.0° C.±0.5°.

In some embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 35% of thegranules are less than about 75 μm. In some embodiments, the rofecoxibor pharmaceutically acceptable salt thereof is formulated into granulesand at least about 55% of the granules are less than about 150 μm. Insome embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 75% of thegranules are less than about 250 μm. In some embodiments, the rofecoxibor pharmaceutically acceptable salt thereof is formulated into granulesand at least about 85% of the granules are less than about 425 μm. Insome embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 90% of thegranules are less than about 1000 μm.

In some embodiments, a 17.5 mg solid dosage formulation of rofecoxibreaches a median time to Cmax plasma concentration in 4 hours or lessfollowing single administration of the formulation to human subjects. Insome embodiments, a 17.5 mg solid dosage formulation of rofecoxibreaches a median time to Cmax plasma concentration in 3 hours or lessfollowing administration. In some embodiments, a 17.5 mg solid dosageformulation of rofecoxib reaches a median time to Cmax plasmaconcentration in 2.5 hours or less following administration. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib reaches amedian time to Cmax plasma concentration in 2 hours or less followingadministration. In some embodiments, a 17.5 mg solid dosage formulationof rofecoxib has a mean Cmax plasma concentration of more than 100ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean Cmax plasma concentration of more than 150 ng/ml,167 ng/ml, or 190 ng/ml. In some embodiments, a 17.5 mg solid dosageformulation of rofecoxib has a mean Cmax plasma concentration of morethan 200 ng/ml. In some embodiments, a 17.5 mg solid dosage formulationof rofecoxib has a mean Cmax plasma concentration of more than 220ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean Cmax plasma concentration of more than 250 ng/ml.In some embodiments, a 17.5 mg solid dosage formulation of rofecoxib hasa mean Cmax plasma concentration of more than 280 ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 1750 h*ng/ml. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib has a mean AUC_(0-∞) of more than2000 h*ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean AUC_(0-∞) of more than 2500 h*ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 3000 h*ng/ml. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib has a mean AUC_(0-∞) of more than3100 h*ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean AUC_(0-∞) of more than 3500 h*ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 4000 h*ng/ml. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib has a mean AUC_(0-∞) of more than4500 h*ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib reaches a Cmax plasma concentration of least 167 ng/ml, 170ng/ml, 175 ng/ml, 180 ng/ml, or higher following single administrationof the formulation to a human subject. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib reaches an AUC_(0-∞) of at least2600 h*ng/ml, 2750 h*ng/ml, 2900 h*ng/ml, 3050 h*ng/ml, 3100 h*ng/ml,3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml or higherfollowing single administration of the formulation to a human subject.

In some embodiments, a 20 mg solid dosage formulation of rofecoxibreaches a median time to Cmax plasma concentration in 4 hours or lessfollowing single administration of the formulation to human subjects. Insome embodiments, a 20 mg solid dosage formulation of rofecoxib reachesa median time to Cmax plasma concentration in 3 hours or less followingadministration. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib reaches a median time to Cmax plasma concentration in 2.5hours or less following administration. In some embodiments, a 20 mgsolid dosage formulation of rofecoxib reaches a median time to Cmaxplasma concentration in 2 hours or less following administration. Insome embodiments, a 20 mg solid dosage formulation of rofecoxib has amean Cmax plasma concentration of more than 150 ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 191 ng/ml, 200 ng/ml, 215 ng/ml,or 225 ng/ml. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib has a mean Cmax plasma concentration of more than 250 ng/ml.In some embodiments, a 20 mg solid dosage formulation of rofecoxib has amean Cmax plasma concentration of more than 300 ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 2000 h*ng/ml. In some embodiments, a 20 mg soliddosage formulation of rofecoxib has a mean AUC_(0-∞) of more than 2500h*ng/ml. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib has a mean AUC_(0-∞) of more than 3000 h*ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 3400 h*ng/ml. In some embodiments, a 20 mg soliddosage formulation of rofecoxib has a mean AUC_(0-∞) of more than 3500h*ng/ml. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib has a mean AUC_(0-∞) of more than 4000 h*ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib reaches aCmax plasma concentration of least 190 ng/ml, 205 ng/ml, 220 ng/ml, 235ng/ml, 250 ng/ml, or higher following single administration of theformulation to a human subject. In some embodiments, a 20 mg soliddosage formulation of rofecoxib reaches an AUC_(0-∞) of at least 3000h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800h*ng/ml, 3950 h*ng/ml, or higher following single administration of theformulation to a human subject. In some embodiments, the rofecoxibformulation achieves a mean Cmax plasma concentration within 80% to 125%of 259 ng/ml and a mean AUC_(0-∞) within 80% to 125% of 3550 h*ng/ml. Insome embodiments, the rofecoxib formulation achieves a mean plasmaAUC_(0-∞) of about 2840-4438 h*ng/ml and a mean plasma Cmax of about207-324 ng/ml following oral administration of a single dose of theformulation to a population of healthy adults less than 65 years of agein a fasted state. In some embodiments, the population of healthy adultsare less than 60 years of age.

In some embodiments, a 25 mg solid dosage formulation of rofecoxibreaches a mean Cmax plasma concentration in less than 3 hours followingsingle administration of the formulation to human subjects. In someembodiments, a 25 mg solid dosage formulation of rofecoxib reaches amean Cmax plasma concentration in less than 2.5 hours followingadministration. In some embodiments, a 25 mg solid dosage formulation ofrofecoxib reaches a mean Cmax plasma concentration in less than 2 hoursfollowing administration. In some embodiments, a 25 mg solid dosageformulation of rofecoxib has a mean Cmax plasma concentration of morethan 240 ng/ml. In some embodiments, a 25 mg solid dosage formulation ofrofecoxib has a mean Cmax plasma concentration of more than 250 ng/ml.In some embodiments, a 25 mg solid dosage formulation of rofecoxib has amean Cmax plasma concentration of more than 300 ng/ml. In someembodiments, a 25 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 320 ng/ml. In some embodiments, a25 mg solid dosage formulation of rofecoxib has a mean AUC_(0-∞) of morethan 4250 h*ng/ml. In some embodiments, a 25 mg solid dosage formulationof rofecoxib has a mean AUC_(0-∞) of more than 4500 h*ng/ml. In someembodiments, a 25 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 4550 h*ng/ml. In some embodiments, a 25 mg soliddosage formulation of rofecoxib has a mean AUC_(0-∞) of more than 4700h*ng/ml. In some embodiments, a 25 mg solid dosage formulation ofrofecoxib reaches a mean Cmax plasma concentration of more than 240ng/ml in a median time of about 3 hours or less following administrationwith an AUC_(0-∞) of more than 4250 h*ng/ml.

In certain aspects, a 10 mg to 50 mg solid dosage formulation ofrofecoxib achieves a mean Cmax plasma concentration from 9.8 ng/ml to 16ng/ml for each 1 mg of rofecoxib in the formulation following singleadministration of the formulation to human subjects. In someembodiments, the 10 mg to 50 mg solid dosage formulation of rofecoxibachieves a mean Cmax plasma concentration from 10 ng/ml to 14 ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, the 10mg to 50 mg solid dosage formulation of rofecoxib achieves a mean Cmaxplasma concentration from 10 ng/ml to 13 ng/ml for each 1 mg ofrofecoxib in the formulation. In some embodiments, the 10 mg to 50 mgsolid dosage formulation achieves a mean Cmax plasma concentration from80% to 125% of 12.8 ng/ml. In some embodiments, the 10 mg to 50 mg soliddosage formulation of rofecoxib reaches a mean AUC_(0-∞) of 170 h*ng/mlto 235 h*ng/ml for each 1 mg of rofecoxib in the formulation. In someembodiments, the 10 mg to 50 mg solid dosage formulation of rofecoxibreaches a mean AUC_(0-∞) of 170 h*ng/ml to 225 h*ng/ml for each 1 mg ofrofecoxib in the formulation. In some embodiments, the formulationachieves a mean AUC_(0-∞) of 177 h*ng/ml to 225 h*ng/ml for each 1 mg ofrofecoxib in the formulation. In some embodiments, the formulationachieves a mean AUC_(0-∞) of 180 h*ng/ml to 225 h*ng/ml for each 1 mg ofrofecoxib in the formulation. In some embodiments, the 10 mg to 50 mgsolid dosage formulation of rofecoxib reaches a mean AUC_(0-∞) of 190h*ng/ml to 215 h*ng/ml for each 1 mg of rofecoxib in the formulation.

In certain aspects, the subject matter disclosed herein provides amethod for treating one or more conditions in a subject in need thereof,the method comprising administering to the subject a solid dosage formcomprising a granular component and an extragranular component, whereinthe granular component comprises an intragranular component comprising17.5 mg of rofecoxib or a pharmaceutically acceptable salt thereof. Insome embodiments, the formulation achieves a median time to Cmax plasmaconcentration in 4 hours or less following single administration of theformulation to human subjects. In some embodiments, the formulationachieves a median time to Cmax plasma concentration in 3 hours or lessfollowing administration. In some embodiments, the formulation achievesa median time to Cmax plasma concentration in 2.5 hours or lessfollowing administration. In some embodiments, the formulation achievesa median time to Cmax plasma concentration in 2 hours or less followingadministration. In some embodiments, the formulation achieves a meanCmax plasma concentration of more than 100 ng/ml. In some embodiments,the formulation achieves a mean Cmax plasma concentration of more than150 ng/ml, 167 ng/ml, or 190 ng/ml. In some embodiments, the formulationachieves a mean Cmax plasma concentration of more than 200 ng/ml. Insome embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 220 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 250ng/ml. In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 280 ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 1750 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 2000h*ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞)of more than 2500 h*ng/ml. In some embodiments, the formulation achievesa mean AUC_(0-∞) of more than 3000 h*ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 3100 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 3500h*ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞)of more than 4000 h*ng/ml. In some embodiments, the formulation achievesa mean AUC_(0-∞) of more than 4500 h*ng/ml. In some embodiments, theformulation reaches a Cmax plasma concentration of least 167 ng/ml, 170ng/ml, 175 ng/ml, 180 ng/ml, or higher following single administrationof the formulation to a human subject. In some embodiments, theformulation reaches an AUC_(0-∞) of at least 2600 h*ng/ml, 2750 h*ng/ml,2900 h*ng/ml, 3050 h*ng/ml, 3100 h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml,3500 h*ng/ml, 3650 h*ng/ml or higher following single administration ofthe formulation to a human subject.

In certain aspects, the subject matter disclosed herein provides amethod for treating one or more conditions in a subject in need thereof,the method comprising administering to the subject a solid dosage formcomprising a granular component and an extragranular component, whereinthe granular component comprises an intragranular component comprising20 mg of rofecoxib or a pharmaceutically acceptable salt thereof. Insome embodiments, the formulation achieves a median time to Cmax plasmaconcentration in 4 hours or less following single administration of theformulation to human subjects. In some embodiments, the formulationachieves a median time to Cmax plasma concentration in 3 hours or lessfollowing administration. In some embodiments, the formulation achievesa median time to Cmax plasma concentration in 2.5 hours or lessfollowing administration. In some embodiments, the formulation achievesa median time to Cmax plasma concentration in 2 hours or less followingadministration. In some embodiments, the formulation achieves a meanCmax plasma concentration of more than 150 ng/ml. In some embodiments,the formulation achieves a mean Cmax plasma concentration of more than191 ng/ml, 200 ng/ml, 215 ng/ml, or 225 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 250ng/ml. In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 258 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 300ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞) ofmore than 2000 h*ng/ml. In some embodiments, the formulation achieves amean AUC_(0-∞) of more than 2500 h*ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 3000 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 3400h*ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞)of more than 3500 h*ng/ml. In some embodiments, the formulation achievesa mean AUC_(0-∞) of more than 4000 h*ng/ml. In some embodiments, theformulation reaches a Cmax plasma concentration of least 190 ng/ml, 205ng/ml, 220 ng/ml, 235 ng/ml, 250 ng/ml, or higher following singleadministration of the formulation to a human subject. In someembodiments, the formulation reaches an AUC_(0-∞) of at least 3000h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800h*ng/ml, 3950 h*ng/ml, or higher following single administration of theformulation to a human subject. In some embodiments, the rofecoxibformulation achieves a mean Cmax plasma concentration within 80% to 125%of 259 ng/ml and a mean AUC_(0-∞) within 80% to 125% of 3550 h*ng/ml. Insome embodiments, the rofecoxib formulation achieves a mean plasmaAUC_(0-∞) of about 2840-4438 h*ng/ml and a mean plasma Cmax of about207-324 ng/ml following oral administration of a single dose of theformulation to a population of healthy adults less than 65 years of agein a fasted state. In some embodiments, the population of healthy adultsare less than 60 years of age.

In certain aspects, the subject matter disclosed herein provides amethod for treating one or more conditions in a subject in need thereof,the method comprising administering to the subject a solid dosage formcomprising a granular component and an extragranular component, whereinthe granular component comprises an intragranular component comprising25 mg of rofecoxib or a pharmaceutically acceptable salt thereof. Insome embodiments, the formulation achieves a mean Cmax plasmaconcentration in less than 3 hours following single administration ofthe formulation to human subjects. In some embodiments, the formulationachieves a mean Cmax plasma concentration in less than 2.5 hoursfollowing administration. In some embodiments, the formulation achievesa mean Cmax plasma concentration in less than 2 hours followingadministration. In some embodiments, the formulation achieves a meanCmax plasma concentration of more than 240 ng/ml. In some embodiments,the formulation achieves a mean Cmax plasma concentration of more than250 ng/ml. In some embodiments, the formulation achieves a mean Cmaxplasma concentration of more than 300 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 320ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞) ofmore than 4250 h*ng/ml. In some embodiments, the formulation achieves amean AUC_(0-∞) of more than 4500 h*ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 4550 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 4700h*ng/ml. In some embodiments, the formulation achieves a Cmax plasmaconcentration of more than 240 ng/ml in about 3 hours followingadministration with an AUC_(0-∞) of more than 4250 h*ng/ml.

In certain aspects, the subject matter disclosed herein provides amethod for treating one or more conditions in a subject in need thereof,the method comprising administering to the subject a solid dosage formcomprising a granular component and an extragranular component, whereinthe granular component comprises an intragranular component comprising10 mg to 50 mg of rofecoxib or a pharmaceutically acceptable saltthereof. In some embodiments, the formulation achieves a mean Cmaxplasma concentration from 9.8 ng/ml to 16 ng/ml for each 1 mg ofrofecoxib in the formulation following single administration of theformulation to human subjects. In some embodiments, the formulationachieves a mean Cmax plasma concentration from 10 ng/ml to 14 ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, theformulation achieves a mean Cmax plasma concentration from 10 ng/ml to13 ng/ml for each 1 mg of rofecoxib in the formulation. In someembodiments, the formulation achieves a mean Cmax plasma concentrationfrom 80% to 125% of 12.8 ng/ml. In some embodiments, the formulationreaches a mean AUC_(0-∞) of 170 h*ng/ml to 235 h*ng/ml for each 1 mg ofrofecoxib in the formulation. In some embodiments, the formulationreaches a mean AUC_(0-∞) of 170 h*ng/ml to 225 h*ng/ml for each 1 mg ofrofecoxib in the formulation. In some embodiments, the formulationachieves a mean AUC_(0-∞) of 177 h*ng/ml to 225 h*ng/ml for each 1 mg ofrofecoxib in the formulation. In some embodiments, the formulationachieves a mean AUC_(0-∞) of 180 h*ng/ml to 225 h*ng/ml for each 1 mg ofrofecoxib in the formulation. In some embodiments, the formulationreaches a mean AUC_(0-∞) of 190 h*ng/ml to 215 h*ng/ml for each 1 mg ofrofecoxib in the formulation.

A method for enhancing the dissolution profile of a solid dosage formcomprising rofecoxib or a pharmaceutically acceptable salt thereof, themethod comprising providing a pharmaceutically acceptable formulationcomprising a granular component and an extragranular component, whereinthe granular component comprises an intragranular component comprisingrofecoxib or a pharmaceutically acceptable salt thereof and one or moredisintegrants, and wherein the extragranular component comprises one ormore disintegrants.

In some embodiments, the one or more disintegrants in the granularcomponent is selected from starches, clays, celluloses, algins, gums,cross-linked polymers, and combinations thereof. In some embodiments,the one or more disintegrants in the granular component is selected fromcroscarmellose, crospovidone, sodium starch glycolate, and combinationsthereof. In some embodiments, the one or more disintegrants in thegranular component is croscarmellose sodium. In some embodiments, theone or more disintegrants in the granular component is about 1% (w/w) toabout 8% (w/w) of the formulation. In some embodiments, the one or moredisintegrants in the granular component is about 1% (w/w) to about 6%(w/w) of the formulation. In some embodiments, the one or moredisintegrants in the granular component is about 1% (w/w) to about 4%(w/w) of the formulation.

In some embodiments, the one or more disintegrants in the extragranularcomponent is selected from starches, clays, celluloses, algins, gums,cross-linked polymers, and combinations thereof. In some embodiments,the one or more disintegrants in the extragranular component is selectedfrom croscarmellose, crospovidone, sodium starch glycolate, andcombinations thereof. In some embodiments, the one or more disintegrantsin the extragranular component is croscarmellose sodium. In someembodiments, the disintegrant in the extragranular component is about 1%(w/w) to about 8% (w/w) of the formulation. In some embodiments, thedisintegrant in the extragranular component is about 1% (w/w) to about6% (w/w) of the formulation. In some embodiments, the disintegrant inthe extragranular component is about 1% (w/w) to about 4% (w/w) of theformulation.

In some embodiments, the disintegrant in the granular component and thedisintegrant in the extragranular component are together about 2% (w/w)to about 12% (w/w) of the formulation. In some embodiments, thedisintegrant in the granular component and the disintegrant in theextragranular component are together about 2% (w/w) to about 10% (w/w)of the formulation. In some embodiments, the disintegrant in thegranular component and the disintegrant in the extragranular componentare together about 2% (w/w) to about 8% (w/w) of the formulation.

In some embodiments, the ratio of granular disintegrant to extragranulardisintegrant is about 40% (w/w) to about 60% (w/w). In some embodiments,the ratio of granular disintegrant to extragranular disintegrant isabout 45% (w/w) to about 55% (w/w). In some embodiments, the ratio ofgranular disintegrant to extragranular disintegrant is about 50% (w/w)to about 50% (w/w). In some embodiments, the ratio of granulardisintegrant to extragranular disintegrant is about 55% (w/w) to about45% (w/w). In some embodiments, the ratio of granular disintegrant toextragranular disintegrant is about 60% (w/w) to about 40% (w/w).

In some embodiments, the pharmaceutically acceptable formulation furthercomprising one or more of a diluent, a binder, a coloring agent, and alubricant. In some embodiments, at least a portion of the diluent is inthe granular component. In some embodiments, the diluent is selectedfrom dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin,mannitol, sodium chloride, dry starch, powdered sugar, sorbitol,sucrose, inositol, and combinations thereof. In some embodiments, thediluent is selected from lactose, cellulose, or a combination thereof.In some embodiments, the diluent is selected from lactose monohydrate,microcrystalline cellulose, or a combination thereof.

In some embodiments, the lactose monohydrate is about 35% (w/w) to about45% (w/w) of the formulation. In some embodiments, the lactosemonohydrate is about 37% (w/w) to about 42% (w/w) of the formulation. Insome embodiments, the lactose monohydrate is about 39% (w/w) to about40% (w/w) of the formulation.

In some embodiments, the microcrystalline cellulose is about 35% (w/w)to about 45% (w/w) of the formulation. In some embodiments, themicrocrystalline cellulose is about 37% (w/w) to about 42% (w/w) of theformulation. In some embodiments, the microcrystalline cellulose isabout 39% (w/w) to about 40% (w/w) of the formulation.

In some embodiments, the diluent is about 75% (w/w) to about 85% (w/w)of the formulation. In some embodiments, diluent is about 77% (w/w) toabout 82% (w/w) of the formulation. In some embodiments, the diluent isabout 78% (w/w) to about 80% (w/w) of the formulation.

In some embodiments, at least a portion of the binder is in the granularcomponent. In some embodiments, the binder is selected from starches,gelatins, sugars, gums, waxes, water, alcohols, celluloses, andcombinations thereof. In some embodiments, the binder is selected fromacacia gum, tragacanth, corn starch, methyl cellulose, panwar gum,ghatti gum, mucilage of isapol husks, carboxymethylcellulose,methylcellulose, polyvinylpyrrolidone, sucrose, glucose, dextrose,molasses, lactose, and combinations thereof. In some embodiments, thebinder is hydroxypropyl cellulose. In some embodiments, the binder isabout 1% (w/w) to about 5% (w/w) of the formulation. In someembodiments, binder is about 2% (w/w) to about 4% (w/w) of theformulation. In some embodiments, the binder is about 2.5% (w/w) toabout 3.5% (w/w) of the formulation.

In some embodiments, at least a portion of the coloring agent is in theextragranular component. In some embodiments, the coloring agent ispigment blend yellow. In some embodiments, the coloring agent is about0.30% (w/w) to about 0.60% (w/w) of the formulation.

In some embodiments, at least a portion of the lubricant is in theextragranular component. In some embodiments, the lubricant is selectedfrom talc, magnesium stearate, calcium stearate, stearic acid, metallicstearate, hydrogenated vegetable oils, and polyethylene glycol, cornstarch, boric acids, sodium chloride, sodium lauryl sulphate. In someembodiments, the lubricant is magnesium stearate. In some embodiments,the lubricant is about 0.10% (w/w) to about 1% (w/w) of the formulation.In some embodiments, the lubricant is about 0.50% (w/w) of theformulation.

In some embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is about 5% (w/w) to about 30% (w/w) of the formulation. In someembodiments, the rofecoxib or pharmaceutically acceptable salt thereofis about 10% (w/w) to about 20% (w/w) of the formulation. In someembodiments, the rofecoxib or pharmaceutically acceptable salt thereofis about 12% (w/w) to about 13% (w/w) of the formulation. In someembodiments, the formulation comprises about 10 mg of the rofecoxib orpharmaceutically acceptable salt thereof. In some embodiments, theformulation comprises about 10.5 mg of the rofecoxib or pharmaceuticallyacceptable salt thereof. In some embodiments, the formulation comprisesabout 11 mg of the rofecoxib or pharmaceutically acceptable saltthereof. In some embodiments, the formulation comprises about 11.5 mg ofthe rofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the formulation comprises about 12 mg of the rofecoxib orpharmaceutically acceptable salt thereof. In some embodiments, theformulation comprises about 12.5 mg of the rofecoxib or pharmaceuticallyacceptable salt thereof. In some embodiments, the formulation comprisesabout 17.5 mg of the rofecoxib or pharmaceutically acceptable saltthereof. In some embodiments, the formulation comprises about 20 mg ofthe rofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the formulation comprises about 21 mg of the rofecoxib orpharmaceutically acceptable salt thereof. In some embodiments, theformulation comprises about 22 mg of the rofecoxib or pharmaceuticallyacceptable salt thereof. In some embodiments, the formulation comprisesabout 22.5 mg of the rofecoxib or pharmaceutically acceptable saltthereof. In some embodiments, the formulation comprises about 25 mg ofthe rofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the formulation comprises about 50 mg of the rofecoxib orpharmaceutically acceptable salt thereof.

In some embodiments, the rofecoxib is highly pure. In some embodiments,the highly pure rofecoxib comprises less than about 0.1% totalimpurities. In some embodiments, the highly pure rofecoxib comprisesless than about 0.075% total impurities. In some embodiments, the highlypure rofecoxib comprises less than about 0.050% total impurities. Insome embodiments, the highly pure rofecoxib comprises less than about0.025% total impurities. In some embodiments, the highly pure rofecoxibcomprises less than about 0.001% total impurities.

In some embodiments, the highly pure rofecoxib comprises less than about0.10%, 0.05%, 0.02%, or 0.01% of4-[4-(methylsulphonyl)phenyl]-3-phenyl-2,5-furandione. In someembodiments, the highly pure rofecoxib comprises less than about 0.10%,0.05%, 0.02%, or 0.01% of4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some embodiments,the highly pure rofecoxib comprises less than about 0.10%, 0.05%, 0.02%,or 0.01% of 4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In someembodiments, the highly pure rofecoxib comprises less than about 0.10%,0.05%, 0.02%, or 0.01% of4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone.

In some embodiments, the formulation is suitable for oraladministration. In some embodiments, the formulation is an oral tablet.In some embodiments, the oral tablet provides a dissolution rate of atleast about 80% of the rofecoxib or pharmaceutically acceptable saltthereof by about 15 minutes. In some embodiments, the oral tabletprovides a dissolution rate of at least about 85% of the rofecoxib orpharmaceutically acceptable salt thereof by about 15 minutes. In someembodiments, the oral tablet provides a dissolution rate of at leastabout 90% of the rofecoxib or pharmaceutically acceptable salt thereofby about 15 minutes. In some embodiments, the oral tablet provides adissolution rate of at least about 95% of the rofecoxib orpharmaceutically acceptable salt thereof by about 15 minutes. In someembodiments, the oral tablet provides a dissolution rate of at leastabout 100% of the rofecoxib or pharmaceutically acceptable salt thereofby about 15 minutes.

In some embodiments, the dissolution rate is measured in about 1% SDS ata paddle speed of about 50 rpm and at a temperature of about 37.0°C.±0.5° C. In some embodiments, the dissolution rate is measured inabout 1% SDS at a paddle speed of about 75 rpm and at a temperature ofabout 37.0° C.±0.5° C. In some embodiments, the dissolution rate ismeasured in about 1.5% SDS at a paddle speed of about 50 rpm and at atemperature of about 37.0° C.±0.5° C. In some embodiments, thedissolution rate is measured in about 1.5% SDS at a paddle speed ofabout 75 rpm and at a temperature of about 37.0° C.±0.5° C. In someembodiments, the dissolution rate is measured in about 2% SDS at apaddle speed of about 50 rpm and at a temperature of about 37.0° C.±0.5°C. In some embodiments, the dissolution rate is measured in about 2% SDSat a paddle speed of about 75 rpm and at a temperature of about 37.0°C.±0.5° C. In some embodiments, the dissolution rate is measured using aUSP Type II apparatus. In some embodiments, the dissolution rate ismeasured with a USP Type II apparatus using 900 mL of 2% SDS, a paddlespeed of 50 rpm, and a temperature of 37.0° C.±0.5°.

In some embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 35% of thegranules are less than about 75 μm. In some embodiments, the rofecoxibor pharmaceutically acceptable salt thereof is formulated into granulesand at least about 55% of the granules are less than about 150 μm. Insome embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 75% of thegranules are less than about 250 μm. In some embodiments, the rofecoxibor pharmaceutically acceptable salt thereof is formulated into granulesand at least about 85% of the granules are less than about 425 μm. Insome embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 90% of thegranules are less than about 1000 μm.

In some embodiments, a 17.5 mg solid dosage formulation of rofecoxibreaches a median time to Cmax plasma concentration in 4 hours or lessfollowing single administration of the formulation to human subjects. Insome embodiments, a 17.5 mg solid dosage formulation of rofecoxibreaches a median time to Cmax plasma concentration in 3 hours or lessfollowing administration. In some embodiments, a 17.5 mg solid dosageformulation of rofecoxib reaches a mean Cmax plasma concentration inless than 2.5 hours following administration. In some embodiments, a17.5 mg solid dosage formulation of rofecoxib reaches a mean Cmax plasmaconcentration in less than 2.5 hours following administration. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 100 ng/ml. In some embodiments, a17.5 mg solid dosage formulation of rofecoxib has a mean Cmax plasmaconcentration of more than 150 ng/ml, 167 ng/ml, or 190 ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 200 ng/ml. In some embodiments, a17.5 mg solid dosage formulation of rofecoxib has a mean Cmax plasmaconcentration of more than 220 ng/ml. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib has a mean Cmax plasmaconcentration of more than 250 ng/ml. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib has a mean Cmax plasmaconcentration of more than 280 ng/ml. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib has a mean AUC_(0-∞) of more than1750 h*ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean AUC_(0-∞) of more than 2000 h*ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 2500 h*ng/ml. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib has a mean AUC_(0-∞) of more than3000 h*ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean AUC_(0-∞) of more than 3100 h*ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 3500 h*ng/ml. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib has a mean AUC_(0-∞) of more than4000 h*ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean AUC_(0-∞) of more than 4500 h*ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib reaches aCmax plasma concentration of least 167 ng/ml, 170 ng/ml, 175 ng/ml, 180ng/ml, or higher following single administration of the formulation to ahuman subject. In some embodiments, a 17.5 mg solid dosage formulationof rofecoxib reaches an AUC_(0-∞) of at least 2600 h*ng/ml, 2750h*ng/ml, 2900 h*ng/ml, 3050 h*ng/ml, 3100 h*ng/ml, 3200 h*ng/ml, 3350h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml or higher following singleadministration of the formulation to a human subject.

In some embodiments, a 20 mg solid dosage formulation of rofecoxibreaches a median time to Cmax plasma concentration in 4 hours or lessfollowing single administration of the formulation to human subjects. Insome embodiments, a 20 mg solid dosage formulation of rofecoxib reachesa median time to Cmax plasma concentration in 3 hours or less followingadministration. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib reaches a median time to Cmax plasma concentration in 2.5hours or less following administration. In some embodiments, a 20 mgsolid dosage formulation of rofecoxib reaches a median time to Cmaxplasma concentration in 2 hours or less following administration. Insome embodiments, a 20 mg solid dosage formulation of rofecoxib has amean Cmax plasma concentration of more than 150 ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 191 ng/ml, 200 ng/ml, 215 ng/ml,or 225 ng/ml. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib has a mean Cmax plasma concentration of more than 250 ng/ml.In some embodiments, a 20 mg solid dosage formulation of rofecoxib has amean Cmax plasma concentration of more than 258 ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 300 ng/ml. In some embodiments, a20 mg solid dosage formulation of rofecoxib has a mean AUC_(0-∞) of morethan 2000 h*ng/ml. In some embodiments, a 20 mg solid dosage formulationof rofecoxib has a mean AUC_(0-∞) of more than 2500 h*ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 3000 h*ng/ml. In some embodiments, a 20 mg soliddosage formulation of rofecoxib has a mean AUC_(0-∞) of more than 3400h*ng/ml. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib has a mean AUC_(0-∞) of more than 3500 h*ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 4000 h*ng/ml. In some embodiments, a 20 mg soliddosage formulation of rofecoxib reaches a Cmax plasma concentration ofleast 190 ng/ml, 205 ng/ml, 220 ng/ml, 235 ng/ml, 250 ng/ml, or higherfollowing single administration of the formulation to a human subject.In some embodiments, a 20 mg solid dosage formulation of rofecoxibreaches an AUC_(0-∞) of at least 3000 h*ng/ml, 3200 h*ng/ml, 3350h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800 h*ng/ml, 3950 h*ng/ml, orhigher following single administration of the formulation to a humansubject. In some embodiments, the rofecoxib formulation achieves a meanCmax plasma concentration within 80% to 125% of 259 ng/ml and a meanAUC_(0-∞) within 80% to 125% of 3550 h*ng/ml. In some embodiments, therofecoxib formulation achieves a mean plasma AUC_(0-∞) of about2840-4438 h*ng/ml and a mean plasma Cmax of about 207-324 ng/mlfollowing oral administration of a single dose of the formulation to apopulation of healthy adults less than 65 years of age in a fastedstate. In some embodiments, the population of healthy adults are lessthan 60 years of age.

In some embodiments, a 25 mg solid dosage formulation of rofecoxibreaches a mean Cmax plasma concentration in less than 3 hours followingsingle administration of the formulation to human subjects. In someembodiments, a 25 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 240 ng/ml. In some embodiments, a25 mg solid dosage formulation of rofecoxib has a mean Cmax plasmaconcentration of more than 250 ng/ml. In some embodiments, a 25 mg soliddosage formulation of rofecoxib has a mean Cmax plasma concentration ofmore than 300 ng/ml. In some embodiments, a 25 mg solid dosageformulation of rofecoxib has a mean Cmax plasma concentration of morethan 320 ng/ml. In some embodiments, a 25 mg solid dosage formulation ofrofecoxib has a mean AUC_(0-∞) of more than 4250 h*ng/ml. In someembodiments, a 25 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 4500 h*ng/ml. In some embodiments, a 25 mg soliddosage formulation of rofecoxib has a mean AUC_(0-∞) of more than 4550h*ng/ml. In some embodiments, a 25 mg solid dosage formulation ofrofecoxib has a mean AUC_(0-∞) of more than 4700 h*ng/ml. In someembodiments, a 25 mg solid dosage formulation of rofecoxib reaches amean Cmax plasma concentration of more than 240 ng/ml in about 3 hoursfollowing administration with an AUC_(0-∞) of more than 4250 h*ng/ml.

In certain aspects, a 10 mg to 50 mg solid dosage formulation ofrofecoxib achieves a mean Cmax plasma concentration from 9.8 ng/ml to 16ng/ml for each 1 mg of rofecoxib in the formulation following singleadministration of the formulation to human subjects. In someembodiments, a 10 mg to 50 mg solid dosage formulation of rofecoxibachieves a mean Cmax plasma concentration from 10 ng/ml to 14 ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, a 10 mgto 50 mg solid dosage formulation of rofecoxib achieves a mean Cmaxplasma concentration from 10 ng/ml to 13 ng/ml for each 1 mg ofrofecoxib in the formulation. In some embodiments, a 10 mg to 50 mgsolid dosage formulation of rofecoxib achieves a mean Cmax plasmaconcentration from 80% to 125% of 12.8 ng/ml. In some embodiments, a 10mg to 50 mg solid dosage formulation of rofecoxib reaches a meanAUC_(0-∞) of 170 h*ng/ml to 235 h*ng/ml for each 1 mg of rofecoxib inthe formulation. In some embodiments, a 10 mg to 50 mg solid dosageformulation of rofecoxib reaches a mean AUC_(0-∞) of 170 h*ng/ml to 225h*ng/ml for each 1 mg of rofecoxib in the formulation. In someembodiments, a 10 mg to 50 mg solid dosage formulation achieves a meanAUC_(0-∞) of 177 h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib inthe formulation. In some embodiments, a 10 mg to 50 mg solid dosageformulation achieves a mean AUC_(0-∞) of 180 h*ng/ml to 225 h*ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, a 10 mgto 50 mg solid dosage formulation of rofecoxib reaches a mean AUC_(0-∞)of 190 h*ng/ml to 215 h*ng/ml for each 1 mg of rofecoxib in theformulation.

In certain aspects, the subject matter disclosed herein provides amethod for enhancing the dissolution profile of a solid dosage formcomprising rofecoxib or a pharmaceutically acceptable salt thereof, themethod comprising providing a pharmaceutically acceptable formulationcomprising a granular component and an extragranular component, whereinthe granular component comprises an intragranular component comprising17.5 mg of rofecoxib or a pharmaceutically acceptable salt thereof. Insome embodiments, the formulation achieves a median time to Cmax plasmaconcentration in 4 hours or less following single administration of theformulation to human subjects. In some embodiments, the formulationachieves a median time to Cmax plasma concentration in 3 hours or lessfollowing administration. In some embodiments, the formulation achievesa median time to Cmax plasma concentration in 2.5 hours or lessfollowing administration. In some embodiments, the formulation achievesa median time to Cmax plasma concentration in 2 hours or less followingadministration. In some embodiments, the formulation achieves a meanCmax plasma concentration of more than 100 ng/ml. In some embodiments,the formulation achieves a mean Cmax plasma concentration of more than150 ng/ml, 167 ng/ml, or 190 ng/ml. In some embodiments, the formulationachieves a mean Cmax plasma concentration of more than 200 ng/ml. Insome embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 220 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 250ng/ml. In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 280 ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 1750 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 2000h*ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞)of more than 2500 h*ng/ml. In some embodiments, the formulation achievesa mean AUC_(0-∞) of more than 3000 h*ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 3100 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 3500h*ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞)of more than 4000 h*ng/ml. In some embodiments, the formulation achievesa mean AUC_(0-∞) of more than 4500 h*ng/ml. In some embodiments, theformulation reaches a Cmax plasma concentration of least 167 ng/ml, 170ng/ml, 175 ng/ml, 180 ng/ml, or higher following single administrationof the formulation to a human subject. In some embodiments, theformulation reaches an AUC_(0-∞) of at least 2600 h*ng/ml, 2750 h*ng/ml,2900 h*ng/ml, 3050 h*ng/ml, 3100 h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml,3500 h*ng/ml, 3650 h*ng/ml or higher following single administration ofthe formulation to a human subject.

In certain aspects, the subject matter disclosed herein provides amethod for enhancing the dissolution profile of a solid dosage formcomprising rofecoxib or a pharmaceutically acceptable salt thereof, themethod comprising providing a pharmaceutically acceptable formulationcomprising a granular component and an extragranular component, whereinthe granular component comprises an intragranular component comprising20 mg of rofecoxib or a pharmaceutically acceptable salt thereof. Insome embodiments, the formulation achieves a median time to Cmax plasmaconcentration in 4 hours or less following single administration of theformulation to human subjects. In some embodiments, the formulationachieves a median time to Cmax plasma concentration in 3 hours or lessfollowing administration. In some embodiments, the formulation achievesa median time to Cmax plasma concentration in 2.5 hours or lessfollowing administration. In some embodiments, the formulation achievesa median time to Cmax plasma concentration in 2 hours or less followingadministration. In some embodiments, the formulation achieves a meanCmax plasma concentration of more than 150 ng/ml. In some embodiments,the formulation achieves a mean Cmax plasma concentration of more than191 ng/ml, 200 ng/ml, 215 ng/ml, or 225 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 250ng/ml. In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 258 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 300ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞) ofmore than 2000 h*ng/ml. In some embodiments, the formulation achieves amean AUC_(0-∞) of more than 2500 h*ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 3000 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 3400h*ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞)of more than 3500 h*ng/ml. In some embodiments, the formulation achievesa mean AUC_(0-∞) of more than 4000 h*ng/ml. In some embodiments, theformulation reaches a Cmax plasma concentration of least 190 ng/ml, 205ng/ml, 220 ng/ml, 235 ng/ml, 250 ng/ml, or higher following singleadministration of the formulation to a human subject. In someembodiments, the formulation reaches an AUC_(0-∞) of at least 3000h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800h*ng/ml, 3950 h*ng/ml, or higher following single administration of theformulation to a human subject.

In certain aspects, the subject matter disclosed herein provides amethod for enhancing the dissolution profile of a solid dosage formcomprising rofecoxib or a pharmaceutically acceptable salt thereof, themethod comprising providing a pharmaceutically acceptable formulationcomprising a granular component and an extragranular component, whereinthe granular component comprises an intragranular component comprising25 mg solid dosage formulation of rofecoxib or a pharmaceuticallyacceptable salt thereof. In some embodiments, the formulation achieves amean Cmax plasma concentration in less than 3 hours following singleadministration of the formulation to human subjects. In someembodiments, the formulation achieves a mean Cmax plasma concentrationin less than 2.5 hours following administration. In some embodiments,the formulation achieves a mean Cmax plasma concentration in less than 2hours following administration. In some embodiments, the formulationachieves a mean Cmax plasma concentration of more than 240 ng/ml. Insome embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 250 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 300ng/ml. In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 320 ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 4250 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 4500h*ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞)of more than 4550 h*ng/ml. In some embodiments, the formulation achievesa mean AUC_(0-∞) of more than 4700 h*ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 240ng/ml in less than 3 hours following administration with an AUC_(0-∞) ofmore than 4250 h*ng/ml.

In certain aspects, the subject matter disclosed herein provides amethod for enhancing the dissolution profile of a solid dosage formcomprising rofecoxib or a pharmaceutically acceptable salt thereof, themethod comprising providing a pharmaceutically acceptable formulationcomprising a granular component and an extragranular component, whereinthe granular component comprises an intragranular component comprising10 mg to 50 mg of rofecoxib or a pharmaceutically acceptable saltthereof. In some embodiments, the formulation achieves a mean Cmaxplasma concentration from 9.8 ng/ml to 16 ng/ml for each 1 mg ofrofecoxib in the formulation following single administration of theformulation to human subjects. In some embodiments, the formulationachieves a mean Cmax plasma concentration from 10 ng/ml to 14 ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, theformulation achieves a mean Cmax plasma concentration from 10 ng/ml to13 ng/ml for each 1 mg of rofecoxib in the formulation. In someembodiments, the formulation achieves a mean Cmax plasma concentrationfrom 80% to 125% of 12.8 ng/ml. In some embodiments, the formulationreaches a mean AUC_(0-∞) of 170 h*ng/ml to 235 h*ng/ml for each 1 mg ofrofecoxib in the formulation. In some embodiments, the formulationreaches a mean AUC_(0-∞) of 170 h*ng/ml to 225 h*ng/ml for each 1 mg ofrofecoxib in the formulation. In some embodiments, the formulationachieves a mean AUC_(0-∞) of 177 h*ng/ml to 225 h*ng/ml for each 1 mg ofrofecoxib in the formulation. In some embodiments, the formulationachieves a mean AUC_(0-∞) of 180 h*ng/ml to 225 h*ng/ml for each 1 mg ofrofecoxib in the formulation. In some embodiments, the formulationreaches a mean AUC_(0-∞) of 190 h*ng/ml to 215 h*ng/ml for each 1 mg ofrofecoxib in the formulation.

A method for manufacturing a solid dosage form comprising rofecoxib or apharmaceutically acceptable salt thereof, the method comprisingproviding a pharmaceutically acceptable formulation comprising agranular component and an extragranular component, wherein the granularcomponent comprises an intragranular component comprising rofecoxib or apharmaceutically acceptable salt thereof and one or more disintegrants,and wherein the extragranular component comprises one or moredisintegrants.

In some embodiments, the one or more disintegrants in the granularcomponent is selected from starches, clays, celluloses, algins, gums,cross-linked polymers, and combinations thereof. In some embodiments,the one or more disintegrants in the granular component is selected fromcroscarmellose, crospovidone, sodium starch glycolate, and combinationsthereof. In some embodiments, the one or more disintegrants in thegranular component is croscarmellose sodium. In some embodiments, theone or more disintegrants in the granular component is about 1% (w/w) toabout 8% (w/w) of the formulation. In some embodiments, the one or moredisintegrants in the granular component is about 1% (w/w) to about 6%(w/w) of the formulation. In some embodiments, the one or moredisintegrants in the granular component is about 1% (w/w) to about 4%(w/w) of the formulation.

In some embodiments, the one or more disintegrants in the extragranularcomponent is selected from starches, clays, celluloses, algins, gums,cross-linked polymers, and combinations thereof. In some embodiments,the one or more disintegrants in the extragranular component is selectedfrom croscarmellose, crospovidone, sodium starch glycolate, andcombinations thereof. In some embodiments, the one or more disintegrantsin the extragranular component is croscarmellose sodium. In someembodiments, the disintegrant in the extragranular component is about 1%(w/w) to about 8% (w/w) of the formulation. In some embodiments, thedisintegrant in the extragranular component is about 1% (w/w) to about6% (w/w) of the formulation. In some embodiments, the disintegrant inthe extragranular component is about 1% (w/w) to about 4% (w/w) of theformulation.

In some embodiments, the disintegrant in the granular component and thedisintegrant in the extragranular component are together about 2% (w/w)to about 12% (w/w) of the formulation. In some embodiments, thedisintegrant in the granular component and the disintegrant in theextragranular component are together about 2% (w/w) to about 10% (w/w)of the formulation. In some embodiments, the disintegrant in thegranular component and the disintegrant in the extragranular componentare together about 2% (w/w) to about 8% (w/w) of the formulation.

In some embodiments, the ratio of granular disintegrant to extragranulardisintegrant is about 40% (w/w) to about 60% (w/w). In some embodiments,the ratio of granular disintegrant to extragranular disintegrant isabout 45% (w/w) to about 55% (w/w). In some embodiments, the ratio ofgranular disintegrant to extragranular disintegrant is about 50% (w/w)to about 50% (w/w). In some embodiments, the ratio of granulardisintegrant to extragranular disintegrant is about 55% (w/w) to about45% (w/w). In some embodiments, the ratio of granular disintegrant toextragranular disintegrant is about 60% (w/w) to about 40% (w/w).

In some embodiments, the pharmaceutically acceptable formulation furthercomprising one or more of a diluent, a binder, a coloring agent, and alubricant. In some embodiments, at least a portion of the diluent is inthe granular component. In some embodiments, the diluent is selectedfrom dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin,mannitol, sodium chloride, dry starch, powdered sugar, sorbitol,sucrose, inositol, and combinations thereof. In some embodiments, thediluent is selected from lactose, cellulose, or a combination thereof.In some embodiments, the diluent is selected from lactose monohydrate,microcrystalline cellulose, or a combination thereof.

In some embodiments, the lactose monohydrate is about 35% (w/w) to about45% (w/w) of the formulation. In some embodiments, the lactosemonohydrate is about 37% (w/w) to about 42% (w/w) of the formulation. Insome embodiments, the lactose monohydrate is about 39% (w/w) to about40% (w/w) of the formulation.

In some embodiments, the microcrystalline cellulose is about 35% (w/w)to about 45% (w/w) of the formulation. In some embodiments, themicrocrystalline cellulose is about 37% (w/w) to about 42% (w/w) of theformulation. In some embodiments, the microcrystalline cellulose isabout 39% (w/w) to about 40% (w/w) of the formulation.

In some embodiments, the diluent is about 75% (w/w) to about 85% (w/w)of the formulation. In some embodiments, diluent is about 77% (w/w) toabout 82% (w/w) of the formulation. In some embodiments, the diluent isabout 78% (w/w) to about 80% (w/w) of the formulation.

In some embodiments, at least a portion of the binder is in the granularcomponent. In some embodiments, the binder is selected from starches,gelatins, sugars, gums, waxes, water, alcohols, celluloses, andcombinations thereof. In some embodiments, the binder is selected fromacacia gum, tragacanth, corn starch, methyl cellulose, panwar gum,ghatti gum, mucilage of isapol husks, carboxymethylcellulose,methylcellulose, polyvinylpyrrolidone, sucrose, glucose, dextrose,molasses, lactose, and combinations thereof. In some embodiments, thebinder is hydroxypropyl cellulose. In some embodiments, the binder isabout 1% (w/w) to about 5% (w/w) of the formulation. In someembodiments, binder is about 2% (w/w) to about 4% (w/w) of theformulation. In some embodiments, the binder is about 2.5% (w/w) toabout 3.5% (w/w) of the formulation.

In some embodiments, at least a portion of the coloring agent is in theextragranular component. In some embodiments, the coloring agent ispigment blend yellow. In some embodiments, the coloring agent is about0.30% (w/w) to about 0.60% (w/w) of the formulation.

In some embodiments, at least a portion of the lubricant is in theextragranular component. In some embodiments, the lubricant is selectedfrom talc, magnesium stearate, calcium stearate, stearic acid, metallicstearate, hydrogenated vegetable oils, and polyethylene glycol, cornstarch, boric acids, sodium chloride, sodium lauryl sulphate. In someembodiments, the lubricant is magnesium stearate. In some embodiments,the lubricant is about 0.10% (w/w) to about 1% (w/w) of the formulation.In some embodiments, the lubricant is about 0.50% (w/w) of theformulation.

In some embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is about 5% (w/w) to about 30% (w/w) of the formulation. In someembodiments, the rofecoxib or pharmaceutically acceptable salt thereofis about 10% (w/w) to about 20% (w/w) of the formulation. In someembodiments, the rofecoxib or pharmaceutically acceptable salt thereofis about 12% (w/w) to about 13% (w/w) of the formulation. In someembodiments, the formulation comprises about 10 mg of the rofecoxib orpharmaceutically acceptable salt thereof. In some embodiments, theformulation comprises about 10.5 mg of the rofecoxib or pharmaceuticallyacceptable salt thereof. In some embodiments, the formulation comprisesabout 11 mg of the rofecoxib or pharmaceutically acceptable saltthereof. In some embodiments, the formulation comprises about 11.5 mg ofthe rofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the formulation comprises about 12 mg of the rofecoxib orpharmaceutically acceptable salt thereof. In some embodiments, theformulation comprises about 12.5 mg of the rofecoxib or pharmaceuticallyacceptable salt thereof. In some embodiments, the formulation comprisesabout 17.5 mg of the rofecoxib or pharmaceutically acceptable saltthereof. In some embodiments, the formulation comprises about 20 mg ofthe rofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the formulation comprises about 21 mg of the rofecoxib orpharmaceutically acceptable salt thereof. In some embodiments, theformulation comprises about 22 mg of the rofecoxib or pharmaceuticallyacceptable salt thereof. In some embodiments, the formulation comprisesabout 22.5 mg of the rofecoxib or pharmaceutically acceptable saltthereof. In some embodiments, the formulation comprises about 25 mg ofthe rofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the formulation comprises about 50 mg of the rofecoxib orpharmaceutically acceptable salt thereof.

In some embodiments, the rofecoxib is highly pure. In some embodiments,the highly pure rofecoxib comprises less than about 0.1% totalimpurities. In some embodiments, the highly pure rofecoxib comprisesless than about 0.075% total impurities. In some embodiments, the highlypure rofecoxib comprises less than about 0.050% total impurities. Insome embodiments, the highly pure rofecoxib comprises less than about0.025% total impurities. In some embodiments, the highly pure rofecoxibcomprises less than about 0.001% total impurities.

In some embodiments, the highly pure rofecoxib comprises less than about0.10%, 0.05%, 0.02%, or 0.01% of4-[4-(methylsulphonyl)phenyl]-3-phenyl-2,5-furandione. In someembodiments, the highly pure rofecoxib comprises less than about 0.10%,0.05%, 0.02%, or 0.01% of4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some embodiments,the highly pure rofecoxib comprises less than about 0.10%, 0.05%, 0.02%,or 0.01% of 4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In someembodiments, the highly pure rofecoxib comprises less than about 0.10%,0.05%, 0.02%, or 0.01% of4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone.

In some embodiments, the formulation is suitable for oraladministration. In some embodiments, the formulation is an oral tablet.In some embodiments, the oral tablet provides a dissolution rate of atleast about 80% of the rofecoxib or pharmaceutically acceptable saltthereof by about 15 minutes. In some embodiments, the oral tabletprovides a dissolution rate of at least about 85% of the rofecoxib orpharmaceutically acceptable salt thereof by about 15 minutes. In someembodiments, the oral tablet provides a dissolution rate of at leastabout 90% of the rofecoxib or pharmaceutically acceptable salt thereofby about 15 minutes. In some embodiments, the oral tablet provides adissolution rate of at least about 95% of the rofecoxib orpharmaceutically acceptable salt thereof by about 15 minutes. In someembodiments, the oral tablet provides a dissolution rate of at leastabout 100% of the rofecoxib or pharmaceutically acceptable salt thereofby about 15 minutes.

In some embodiments, the dissolution rate is measured in about 1% SDS ata paddle speed of about 50 rpm and at a temperature of about 37.0°C.±0.5° C. In some embodiments, the dissolution rate is measured inabout 1% SDS at a paddle speed of about 75 rpm and at a temperature ofabout 37.0° C.±0.5° C. In some embodiments, the dissolution rate ismeasured in about 1.5% SDS at a paddle speed of about 50 rpm and at atemperature of about 37.0° C.±0.5° C. In some embodiments, thedissolution rate is measured in about 1.5% SDS at a paddle speed ofabout 75 rpm and at a temperature of about 37.0° C.±0.5° C. In someembodiments, the dissolution rate is measured in about 2% SDS at apaddle speed of about 50 rpm and at a temperature of about 37.0° C.±0.5°C. In some embodiments, the dissolution rate is measured in about 2% SDSat a paddle speed of about 75 rpm and at a temperature of about 37.0°C.±0.5° C. In some embodiments, the dissolution rate is measured using aUSP Type II apparatus. In some embodiments, the dissolution rate ismeasured with a USP Type II apparatus using 900 mL of 2% SDS, a paddlespeed of 50 rpm, and a temperature of 37.0° C.±0.5°.

In some embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 35% of thegranules are less than about 75 μm. In some embodiments, the rofecoxibor pharmaceutically acceptable salt thereof is formulated into granulesand at least about 55% of the granules are less than about 150 μm. Insome embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 75% of thegranules are less than about 250 μm. In some embodiments, the rofecoxibor pharmaceutically acceptable salt thereof is formulated into granulesand at least about 85% of the granules are less than about 425 μm. Insome embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 90% of thegranules are less than about 1000 μm.

In some embodiments, a 17.5 mg solid dosage formulation of rofecoxibreaches a median time to Cmax plasma concentration in 4 hours or lessfollowing single administration of the formulation to human subjects. Insome embodiments, a 17.5 mg solid dosage formulation of rofecoxibreaches a median time to Cmax plasma concentration in 3 hours or lessfollowing administration. In some embodiments, a 17.5 mg solid dosageformulation of rofecoxib reaches a median time to Cmax plasmaconcentration in 2.5 hours or less following administration. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib reaches amedian time to Cmax plasma concentration in 2 hours or less followingadministration. In some embodiments, a 17.5 mg solid dosage formulationof rofecoxib has a mean Cmax plasma concentration of more than 150ng/ml, 167 ng/ml, or 190 ng/ml. In some embodiments, a 17.5 mg soliddosage formulation of rofecoxib has a mean Cmax plasma concentration ofmore than 200 ng/ml. In some embodiments, a 17.5 mg solid dosageformulation of rofecoxib has a mean Cmax plasma concentration of morethan 220 ng/ml. In some embodiments, a 17.5 mg solid dosage formulationof rofecoxib has a mean Cmax plasma concentration of more than 250ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean Cmax plasma concentration of more than 280 ng/ml.In some embodiments, a 17.5 mg solid dosage formulation of rofecoxib hasa mean AUC_(0-∞) of more than 1750 h*ng/ml. In some embodiments, a 17.5mg solid dosage formulation of rofecoxib has a mean AUC_(0-∞) of morethan 2000 h*ng/ml. In some embodiments, a 17.5 mg solid dosageformulation of rofecoxib has a mean AUC_(0-∞) of more than 2500 h*ng/ml.In some embodiments, a 17.5 mg solid dosage formulation of rofecoxib hasa mean AUC_(0-∞) of more than 3000 h*ng/ml. In some embodiments, a 17.5mg solid dosage formulation of rofecoxib has a mean AUC_(0-∞) of morethan 3100 h*ng/ml. In some embodiments, a 17.5 mg solid dosageformulation of rofecoxib has a mean AUC_(0-∞) of more than 3500 h*ng/ml.In some embodiments, a 17.5 mg solid dosage formulation of rofecoxib hasa mean AUC_(0-∞) of more than 4000 h*ng/ml. In some embodiments, a 17.5mg solid dosage formulation of rofecoxib has a mean AUC_(0-∞) of morethan 4500 h*ng/ml. In some embodiments, a 17.5 mg solid dosageformulation of rofecoxib reaches a Cmax plasma concentration of least167 ng/ml, 170 ng/ml, 175 ng/ml, 180 ng/ml, or higher following singleadministration of the formulation to a human subject. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib reaches anAUC_(0-∞) of at least 2600 h*ng/ml, 2750 h*ng/ml, 2900 h*ng/ml, 3050h*ng/ml, 3100 h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650h*ng/ml or higher following single administration of the formulation toa human subject.

In some embodiments, a 20 mg solid dosage formulation of rofecoxibreaches a median time to Cmax plasma concentration in 4 hours or lessfollowing single administration of the formulation to human subjects. Insome embodiments, a 20 mg solid dosage formulation of rofecoxib reachesa median time to Cmax plasma concentration in 3 hours or less followingadministration. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib reaches a median time to Cmax plasma concentration in 2.5hours or less following administration. In some embodiments, a 20 mgsolid dosage formulation of rofecoxib reaches a median time to Cmaxplasma concentration in 2 hours or less following administration. Insome embodiments, a 20 mg solid dosage formulation of rofecoxib has amean Cmax plasma concentration of more than 150 ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 191 ng/ml, 200 ng/ml, 215 ng/ml,or 225 ng/ml. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib has a mean Cmax plasma concentration of more than 250 ng/ml.In some embodiments, a 20 mg solid dosage formulation of rofecoxib has amean Cmax plasma concentration of more than 258 ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 300 ng/ml. In some embodiments, a20 mg solid dosage formulation of rofecoxib has a mean AUC_(0-∞) of morethan 2000 h*ng/ml. In some embodiments, a 20 mg solid dosage formulationof rofecoxib has a mean AUC_(0-∞) of more than 2500 h*ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 3000 h*ng/ml. In some embodiments, a 20 mg soliddosage formulation of rofecoxib has a mean AUC_(0-∞) of more than 3400h*ng/ml. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib has a mean AUC_(0-∞) of more than 3500 h*ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 4000 h*ng/ml. In some embodiments, a 20 mg soliddosage formulation of rofecoxib reaches a Cmax plasma concentration ofleast 190 ng/ml, 205 ng/ml, 220 ng/ml, 235 ng/ml, 250 ng/ml, or higherfollowing single administration of the formulation to a human subject.In some embodiments, a 20 mg solid dosage formulation of rofecoxibreaches an AUC_(0-∞) of at least 3000 h*ng/ml, 3200 h*ng/ml, 3350h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800 h*ng/ml, 3950 h*ng/ml, orhigher following single administration of the formulation to a humansubject. In some embodiments, the rofecoxib formulation achieves a meanCmax plasma concentration within 80% to 125% of 259 ng/ml and a meanAUC_(0-∞) within 80% to 125% of 3550 h*ng/ml. In some embodiments, therofecoxib formulation achieves a mean plasma AUC_(0-∞) of about2840-4438 h*ng/ml and a mean plasma Cmax of about 207-324 ng/mlfollowing oral administration of a single dose of the formulation to apopulation of healthy adults less than 65 years of age in a fastedstate. In some embodiments, the population of healthy adults are lessthan 60 years of age.

In some embodiments, a 25 mg solid dosage formulation of rofecoxibreaches a mean Cmax plasma concentration in less than 3 hours followingsingle administration of the formulation to human subjects. In someembodiments, a 25 mg solid dosage formulation of rofecoxib reaches amean Cmax plasma concentration in less than 2.5 hours followingadministration. In some embodiments, a 25 mg solid dosage formulation ofrofecoxib reaches a mean Cmax plasma concentration in less than 2 hoursfollowing administration. In some embodiments, a 25 mg solid dosageformulation of rofecoxib has a mean Cmax plasma concentration of morethan 240 ng/ml. In some embodiments, a 25 mg solid dosage formulation ofrofecoxib has a mean Cmax plasma concentration of more than 250 ng/ml.In some embodiments, a 25 mg solid dosage formulation of rofecoxib has amean Cmax plasma concentration of more than 300 ng/ml. In someembodiments, a 25 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 320 ng/ml. In some embodiments, a25 mg solid dosage formulation of rofecoxib has a mean AUC_(0-∞) of morethan 4250 h*ng/ml. In some embodiments, a 25 mg solid dosage formulationof rofecoxib has a mean AUC_(0-∞) of more than 4500 h*ng/ml. In someembodiments, a 25 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 4550 h*ng/ml. In some embodiments, a 25 mg soliddosage formulation of rofecoxib has a mean AUC_(0-∞) of more than 4700h*ng/ml. In some embodiments, a 25 mg solid dosage formulation ofrofecoxib reaches a mean Cmax plasma concentration of more than 240ng/ml in a median time of about 3 hours or less following administrationwith an AUC_(0-∞) of more than 4250 h*ng/ml.

In some embodiments, a 10 mg to 50 mg solid dosage formulation ofrofecoxib achieves a mean Cmax plasma concentration from 9.8 ng/ml to 16ng/ml for each 1 mg of rofecoxib in the formulation following singleadministration of the formulation to human subjects. In someembodiments, a 10 mg to 50 mg solid dosage formulation of rofecoxibachieves a mean Cmax plasma concentration from 10 ng/ml to 14 ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, a 10 mgto 50 mg solid dosage formulation of rofecoxib achieves a mean Cmaxplasma concentration from 10 ng/ml to 13 ng/ml for each 1 mg ofrofecoxib in the formulation. In some embodiments, a 10 mg to 50 mgsolid dosage formulation of rofecoxib achieves a mean Cmax plasmaconcentration from 80% to 125% of 12.8 ng/ml. In some embodiments, a 10mg to 50 mg solid dosage formulation of rofecoxib reaches a meanAUC_(0-∞) of 170 h*ng/ml to 235 h*ng/ml for each 1 mg of rofecoxib inthe formulation. In some embodiments, a 10 mg to 50 mg solid dosageformulation of rofecoxib reaches a mean AUC_(0-∞) of 170 h*ng/ml to 225h*ng/ml for each 1 mg of rofecoxib in the formulation. In someembodiments, a 10 mg to 50 mg solid dosage formulation of rofecoxibachieves a mean AUC_(0-∞) of 177 h*ng/ml to 225 h*ng/ml for each 1 mg ofrofecoxib in the formulation. In some embodiments, a 10 mg to 50 mgsolid dosage formulation of rofecoxib achieves a mean AUC_(0-∞) of 180h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib in the formulation. Insome embodiments, a 10 mg to 50 mg solid dosage formulation of rofecoxibreaches a mean AUC_(0-∞) of 190 h*ng/ml to 215 h*ng/ml for each 1 mg ofrofecoxib in the formulation.

In certain aspects, the subject matter disclosed herein provides amethod for manufacturing a solid dosage form comprising rofecoxib or apharmaceutically acceptable salt thereof, the method comprisingproviding a pharmaceutically acceptable formulation comprising agranular component and an extragranular component, wherein the granularcomponent comprises an intragranular component comprising 17.5 mg ofrofecoxib or a pharmaceutically acceptable salt thereof. In someembodiments, the formulation achieves a median time to Cmax plasmaconcentration in 4 hours or less following single administration of theformulation to human subjects. In some embodiments, the formulationachieves a median time to Cmax plasma concentration in 3 hours or lessfollowing administration. In some embodiments, the formulation achievesa median time to Cmax plasma concentration in 2.5 hours or lessfollowing administration. In some embodiments, the formulation achievesa median time to Cmax plasma concentration in 2 hours or less followingadministration. In some embodiments, the formulation achieves a meanCmax plasma concentration of more than 150 ng/ml, 167 ng/ml, or 190ng/ml. In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 200 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 220ng/ml. In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 250 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 280ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞) ofmore than 1750 h*ng/ml. In some embodiments, the formulation achieves amean AUC_(0-∞) of more than 2000 h*ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 2500 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 3000h*ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞)of more than 3100 h*ng/ml. In some embodiments, the formulation achievesa mean AUC_(0-∞) of more than 3500 h*ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 4000 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 4500h*ng/ml. In some embodiments, the formulation reaches a Cmax plasmaconcentration of least 167 ng/ml, 170 ng/ml, 175 ng/ml, 180 ng/ml, orhigher following single administration of the formulation to a humansubject. In some embodiments, the formulation reaches an AUC_(0-∞) of atleast 2600 h*ng/ml, 2750 h*ng/ml, 2900 h*ng/ml, 3050 h*ng/ml, 3100h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml orhigher following single administration of the formulation to a humansubject.

In certain aspects, the subject matter disclosed herein provides amethod for manufacturing a solid dosage form comprising rofecoxib or apharmaceutically acceptable salt thereof, the method comprisingproviding a pharmaceutically acceptable formulation comprising agranular component and an extragranular component, wherein the granularcomponent comprises an intragranular component comprising 20 mg ofrofecoxib or a pharmaceutically acceptable salt thereof. In someembodiments, the formulation achieves a median time to Cmax plasmaconcentration in 4 hours or less following single administration of theformulation to human subjects. In some embodiments, the formulationachieves a median time to Cmax plasma concentration in 3 hours or lessfollowing administration. In some embodiments, the formulation achievesa median time to Cmax plasma concentration in 2.5 hours or lessfollowing administration. In some embodiments, the formulation achievesa median time to Cmax plasma concentration in 2 hours or less followingadministration. In some embodiments, the formulation achieves a meanCmax plasma concentration of more than 150 ng/ml. In some embodiments,the formulation achieves a mean Cmax plasma concentration of more than191 ng/ml, 200 ng/ml, 215 ng/ml, or 225 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 250ng/ml. In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 258 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 300ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞) ofmore than 2000 h*ng/ml. In some embodiments, the formulation achieves amean AUC_(0-∞) of more than 2500 h*ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 3000 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 3400h*ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞)of more than 3500 h*ng/ml. In some embodiments, the formulation achievesa mean AUC_(0-∞) of more than 4000 h*ng/ml. In some embodiments, theformulation reaches a Cmax plasma concentration of least 190 ng/ml, 205ng/ml, 220 ng/ml, 235 ng/ml, 250 ng/ml, or higher following singleadministration of the formulation to a human subject. In someembodiments, the formulation reaches an AUC_(0-∞) of at least 3000h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800h*ng/ml, 3950 h*ng/ml, or higher following single administration of theformulation to a human subject. In some embodiments, the rofecoxibformulation achieves a mean Cmax plasma concentration within 80% to 125%of 259 ng/ml and a mean AUC_(0-∞) within 80% to 125% of 3550 h*ng/ml. Insome embodiments, the rofecoxib formulation achieves a mean plasmaAUC_(0-∞) of about 2840-4438 h*ng/ml and a mean plasma Cmax of about207-324 ng/ml following oral administration of a single dose of theformulation to a population of healthy adults less than 65 years of agein a fasted state. In some embodiments, the population of healthy adultsare less than 60 years of age.

In certain aspects, the subject matter disclosed herein provides amethod for manufacturing a solid dosage form comprising rofecoxib or apharmaceutically acceptable salt thereof, the method comprisingproviding a pharmaceutically acceptable formulation comprising agranular component and an extragranular component, wherein the granularcomponent comprises an intragranular component comprising 25 mg ofrofecoxib or a pharmaceutically acceptable salt thereof. In someembodiments, the formulation achieves a mean Cmax plasma concentrationin less than 3 hours following single administration of the formulationto human subjects. In some embodiments, the formulation achieves a meanCmax plasma concentration in less than 2.5 hours followingadministration. In some embodiments, the formulation achieves a meanCmax plasma concentration in less than 2 hours following administration.In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 240 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 250ng/ml. In some embodiments, the formulation achieves a mean Cmax plasmaconcentration of more than 300 ng/ml. In some embodiments, theformulation achieves a mean Cmax plasma concentration of more than 320ng/ml. In some embodiments, the formulation achieves a mean AUC_(0-∞) ofmore than 4250 h*ng/ml. In some embodiments, the formulation achieves amean AUC_(0-∞) of more than 4500 h*ng/ml. In some embodiments, theformulation achieves a mean AUC_(0-∞) of more than 4550 h*ng/ml. In someembodiments, the formulation achieves a mean AUC_(0-∞) of more than 4700h*ng/ml. In some embodiments, the formulation achieves a Cmax plasmaconcentration of more than 240 ng/ml in about 3 hours followingadministration with an AUC_(0-∞) of more than 4250 h*ng/ml.

In certain aspects, the subject matter disclosed herein provides amethod for manufacturing a solid dosage form comprising rofecoxib or apharmaceutically acceptable salt thereof, the method comprisingproviding a pharmaceutically acceptable formulation comprising agranular component and an extragranular component, wherein the granularcomponent comprises an intragranular component comprising 10 mg to 50 mgof rofecoxib or a pharmaceutically acceptable salt thereof. In someembodiments, the formulation achieves a mean Cmax plasma concentrationfrom 9.8 ng/ml to 16 ng/ml for each 1 mg of rofecoxib in the formulationfollowing single administration of the formulation to human subjects. Insome embodiments, the formulation achieves a mean Cmax plasmaconcentration from 10 ng/ml to 14 ng/ml for each 1 mg of rofecoxib inthe formulation. In some embodiments, the formulation achieves a meanCmax plasma concentration from 10 ng/ml to 13 ng/ml for each 1 mg ofrofecoxib in the formulation. In some embodiments, the formulationachieves a mean Cmax plasma concentration from 80% to 125% of 12.8ng/ml. In some embodiments, the formulation reaches a mean AUC_(0-∞) of170 h*ng/ml to 235 h*ng/ml for each 1 mg of rofecoxib in theformulation. In some embodiments, the formulation reaches a meanAUC_(0-∞) of 177 h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib inthe formulation. In some embodiments, the formulation achieves a meanAUC_(0-∞) of 177 h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib inthe formulation. In some embodiments, the formulation achieves a meanAUC_(0-∞) of 180 h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib inthe formulation. In some embodiments, the formulation reaches a meanAUC_(0-∞) of 190 h*ng/ml to 215 h*ng/ml for each 1 mg of rofecoxib inthe formulation.

Methods for Manufacturing of Rofecoxib Tablets

In some embodiments, the subject matter disclosed herein provides for amethod of manufacture of a 25-mg rofecoxib tablet. In some embodiments,the rofecoxib tablet is a 5-mg rofecoxib tablet, 10-mg rofecoxib tablet,10.5-mg rofecoxib tablet, 11-mg rofecoxib tablet, 11.5-mg rofecoxibtablet, 12-mg rofecoxib tablet, 12.5-mg rofecoxib tablet, 13-mgrofecoxib tablet, 14-mg rofecoxib tablet, 15-mg rofecoxib tablet, 16-mgrofecoxib tablet, 17-mg rofecoxib tablet, 17.5-mg rofecoxib tablet,18-mg rofecoxib tablet, 19-mg rofecoxib tablet, 20-mg rofecoxib tablet,21-mg rofecoxib tablet, 22-mg rofecoxib tablet, 22.5-mg rofecoxibtablet, 25-mg rofecoxib tablet, 30-mg rofecoxib tablet, 40-mg rofecoxibtablet, 50-mg rofecoxib tablet, or 60-mg rofecoxib tablet.

In some embodiments, the composition of the 25-mg rofecoxib tablet andthe function of each excipient are as provided in FIGS. 1A-B. In someembodiments, the manufacturing train includes high-shear wet granulationbecause the micronized drug substance could be prone to powder flowissues during scale-up if a direct compression process was used. Some ofthe different embodiments of the manufacturing process described hereinare referred to Process A₁, Process A₂, Process A₃ or Process B₁.Subscripted numbers denote small differences in the manufacturingprocess between embodiments. Letters denote major differences in themanufacturing process between embodiments.

Process A₁, Process A₂, and Process A₃

In some embodiments, the manufacturing process can be Process A₁,Process A₂, or Process A₃, each with processing conditions as describedin FIG. 2. In some embodiments, Process A₁, Process A₂, or Process A₃result in manufacture of batches 1-4. In some embodiments, dissolutiontesting of batches is performed in two media: 2% SDS and 0.1N HCl at37.0±0.5° C. with a paddle speed of 75 rpm. Dissolution profiles forbatches 1 and 2 are shown in FIGS. 3A-B. The points shown in thedissolution profiles are an average of three tablets, and the 75-minutepoint is an infinity spin in which the paddle speed was increased to 250rpm for 15 minutes following the 60-minute time point. FIG. 3A showsdissolution of rofecoxib tablets in 0.1N HCl. FIG. 3B shows dissolutionof rofecoxib tablets in at least 2% SDS. The results in both mediaindicate that dissolution may be incomplete after 60 minutes, with oneexception being batch 3 in at least 2% SDS. Dissolution profiles forbatches 3 and 4 are shown in FIGS. 4A-B. FIG. 4A shows dissolution ofrofecoxib tablets in 0.1N HCl. FIG. 4B shows dissolution of rofecoxibtablets in at least 2% SDS.

Process B₁

In some embodiments, the manufacturing process of the rofecoxib tabletsis Process B₁. In some embodiments, Process B₁ includes croscarmellolosesodium, a disintegrant, as an intragranular and extragranular componentin order to achieve complete dissolution of rofecoxib. Batches 1-4according to Process A₁₋₃ may include croscarmellolose sodium as anextragranular component. In some embodiments. the processing conditionsof Process B₁ are shown in FIG. 5. In Process B₁, as compared to ProcessA₁₋₃, the pigment amount can be increased from 0.30 to 0.60%, while thepercentage of the diluents is decreased to accommodate increases inpigment or croscarmellose sodium; the ratio of lactose monohydrate tomicrocrystalline cellulose can remain at 1:1. In some embodiments,dissolution testing is performed in at least 2% SDS at 37.0±0.5° C. witha paddle speed of 75 rpm. Dissolution profiles for rofecoxib tabletsmanufactured using Process B₁ in batches 5-8 are shown in FIGS. 6A-B.The results indicate that intragranular disintegrant can improve therate at which rofecoxib dissolves and the extent to which rofecoxibdissolves. The results also indicate that there is no advantage tohaving 8% total disintegrant in the tablet versus 4% total disintegrant.Therefore, in some embodiments, batches 5 and 6 are the leadformulations. Additional dissolution testing of batches 5 and 6 in atleast 2% SDS at 37.0±0.5° C. with a slower paddle speed of 50 rpmindicate that 50 rpm is an appropriate paddle speed for the dissolutiontest as shown in FIG. 7.

Exemplary batch analysis and dissolution profile is presented in Table 1below for 17.5 mg rofecoxib tablets.

TABLE 1 Batch Analysis for 17.5-mg Rofecoxib Tablets Lot No. (manu-Uniformity of facturing Dosage Forms Dissolution, % Dissolved process)Mean Range 10 15 20 30 45 60 minutes % w/w % w/w AV minutes minutesminutes minutes minutes minutes B19056 (B₁) 100.1 99.2-110.9 1.2 89 9798 100 101 101

Exemplary batch analysis and dissolution profile is presented in Table 2below for 20 mg rofecoxib tablets.

TABLE 2 Batch Analysis Data for 20-mg Rofecoxib Tablets Lot No.Uniformity (manu- of Dosage Forms Dissolution, % Dissolved facturingMean Range 10 15 20 30 45 60 process) % w/w % w/w AV minutes minutesminutes minutes minutes minutes B19057 (B₁) 99.7 98.8-100.3 1.2 88 95 9799 100 100

Process B₂

In some embodiments, the manufacturing process of the rofecoxib tabletsis Process B₂. Process B₂ differs from Process B₁ in that, in ProcessB₂, the pigment blend is added during granulation. As a result, thecompositions of the 25-mg rofecoxib tablets manufactured using ProcessesB₁ and B₂ are identical, as only the manufacturing step during whichpigment is added differs. Additional dose strengths can be manufacturedby varying the quantities of the first three components, while keepingthe tablet weight constant at 200 mg. The ratio of microcrystallinecellulose to lactose monohydrate is maintained at 1:1 in all dosestrengths. Exemplary tablets manufactured according to Process B₂ areset forth in Tables 6B and 18.

Formulation and Process for the PK Study

In some embodiments, the amount of pigment in the clinical batch is0.30%. For example, the color of batches 5-8 is only slightly darkerthan the color of batches 1-4, despite having a greater amount ofpigment. Therefore, there may not be any aesthetic advantage to having0.60% pigment in the tablet. Batches 5 and 6, even though they containmore pigment than the clinical batch, are considered representative ofthe clinical batch because all were manufactured using Process B₁ andbecause the composition of the intragranular and extragranulardisintegrant is the same as that for the clinical batch as shown in FIG.8. Additional dose strengths can be manufactured by varying thequantities of the first three components, while keeping the tabletweight constant at 200 mg. The ratio of microcrystalline cellulose tolactose monohydrate is maintained at 1:1 in all dose strengths.

Process descriptions for the manufacture of prototype 25-mg rofecoxibtablets for Process A₁, Process A₂, or Process A₃, and Process B₁ areshown in FIG. 9. FIGS. 10A-B show a flow diagram for rofecoxib tabletmanufacturing Process A₁. FIG. 10A shows manufacture of rofecoxibgranules. FIG. 10B shows manufacture of rofecoxib tablets. FIGS. 11A-Bshow a flow diagram for rofecoxib tablet manufacturing Process A₂. FIG.11A shows manufacture of rofecoxib granules. FIG. 11B shows manufactureof rofecoxib tablets. FIGS. 12A-B show a flow diagram for rofecoxibtablet manufacturing Process A₃. FIG. 12A shows manufacture of rofecoxibgranules. FIG. 12B shows manufacture of rofecoxib tablets. FIGS. 13A-Bshow a flow diagram for rofecoxib tablet manufacturing Process B₁. FIG.13A shows manufacture of rofecoxib granules. FIG. 13B shows manufactureof rofecoxib tablets.

In some embodiments, rofecoxib tablets are administered to patients at aclinical site and are packaged in multi-use HDPE bottles that areinduction sealed and closed with child resistant caps. Each bottle mayalso contain rayon coil USP. In some embodiments, rofecoxib tablets aremanufactured using a wet-granulation process.

In some embodiments, rofecoxib tablets are a solid oral dosage form thatis manufactured using equipment with non-reactive surfaces. In someembodiments, rofecoxib is packaged in standard containers that do notpresent compatibility issues.

The batch formulae for representative 2.3-kg batches of rofecoxibtablets are shown in Table 3 below. In some embodiments, other batchsizes are possible.

TABLE 3 Batch Formula for 25-mg Rofecoxib Tablets Amount, (g) Components25 mg 20 mg 17.5 mg 12.5 mg Rofecoxib^(a) 287.50 230.00 201.25 143.75Lactose monohydrate 916.55 945.30 959.68 988.43 Microcrystallinecellulose 916.55 945.30 959.68 988.43 Hydroxypropylcellulose 69.00 69.0069.00 69.00 Croscarmellose sodium 92.00 92.00 92.00 92.00 Pigment blendyellow 6.90 6.90 6.90 6.90 Magnesium stearate 11.50 11.50 11.50 11.50Water NA^(b) NA^(b) NA^(b) NA^(b) ^(a)Note that the amount of rofecoxibmay be adjusted for purity and moisture content. An adjustment can bemade to the amounts of lactose monohydrate and microcrystallinecellulose used to maintain tablet weight. ^(b)NA = not applicable. Theamount of water for granulation may vary in order to achieve granules;water for granulation is removed upon drying of the wet mass.

Rofecoxib

Rofecoxib (also known as TRM-201; RXB-201; and4-[4-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone) is a nonsteroidalanti-inflammatory drug that exhibits anti-inflammatory, analgesic, andantipyretic activities. Without being bound by theory, the mechanism ofaction of rofecoxib is believed to be due to inhibition of prostaglandinsynthesis, via inhibition of cyclooxygenase-2 (COX-2). Additionally, attherapeutic concentrations in humans, rofecoxib does not inhibit thecyclooxygenase-1 (COX-1) isoenzyme.

Rofecoxib is a potent inhibitor of prostaglandin synthesis in vitro.Prostaglandins are mediators of inflammation. Rofecoxib concentrationsreached during therapy have produced in vivo effects. Prostaglandinssensitize afferent nerves and potentiate the action of bradykinin ininducing pain in animal models. Because rofecoxib is an inhibitor ofprostaglandin synthesis, its mode of action may be due to a decrease ofprostaglandins in peripheral tissues.

In some embodiments, rofecoxib is indicated: for relief of the signs andsymptoms of osteoarthritis, for relief of the signs and symptoms ofrheumatoid arthritis in adults, for relief of the signs and symptoms ofpauciarticular or polyarticular course Juvenile Rheumatoid Arthritis(JRA) in patients 2 years and older and who weigh 10 kg (22 lbs) ormore, for the management of acute pain in adults, for the treatment ofprimary dysmenorrhea, for the acute treatment of migraine attacks withor without aura in adults. In some embodiments, rofecoxib is used totreat lower back pain, including chronic lower back pain, and psoriaticarthritis.

The chemical structure of rofecoxib is shown below. Rofecoxib bears nochiral centers and has a molecular weight of 314.355 g moL⁻¹.

In some embodiments, rofecoxib is a white to off-white to light yellowpowder. In some embodiments, rofecoxib is sparingly soluble in acetone,slightly soluble in methanol and isopropyl acetate, very slightlysoluble in ethanol, practically insoluble in octanol, and insoluble inwater. In some embodiments, each tablet of rofecoxib for oraladministration contains either 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg,12.5 mg, 17.5 mg, 20 mg, 21 mg, 22 mg, 22.5 mg, 25 mg, or 50 mg ofrofecoxib and the following inactive ingredients: croscarmellose sodium,hydroxypropyl cellulose, lactose, magnesium stearate, microcrystallinecellulose, and yellow ferric oxide. The 50 mg tablets may also containred ferric oxide. In some embodiments, each 5 mL of the oral suspensioncontains 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 17.5 mg, 20 mg,21 mg, 22 mg, 22.5 mg 25 mg, or 50 mg of rofecoxib and the followinginactive ingredients: citric acid (monohydrate), sodium citrate(dihydrate), sorbitol solution, strawberry flavor, xanthan gum, andpurified water. Added as preservatives are sodium methylparaben about0.13% and sodium propylparaben about 0.02%.

In some embodiments, the rofecoxib or pharmaceutically acceptable saltthereof is about 1%, about 5% (w/w), about 10% (w/w), about 15% (w/w),about 20% (w/w), about 25% (w/w), about 30% (w/w), about 35% (w/w), orabout 40% (w/w) of the formulation. In some embodiments, the formulationcomprises about 5 mg, about 8 mg, about 10 mg, about 10.5 mg, about 11mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 15 mg, about 17.5mg, or about 20 mg of the rofecoxib or pharmaceutically acceptable saltthereof. In some embodiments, the formulation comprises about 20 mg, 21mg, 22 mg, 22.5 mg. In some embodiments, the formulation comprises about23 mg, about 25 mg, about 27 mg, about 30 mg, about 35 mg, or about 40mg of the rofecoxib or pharmaceutically acceptable salt thereof. In someembodiments, the formulation comprises about 45 mg, about 47 mg, about50 mg, about 53 mg, about 55 mg, about 60 mg of the rofecoxib orpharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutically acceptable formulation asdescribed here includes highly pure rofecoxib, which is essentially freeor free of one or more of the impurities found in previously availablerofecoxib bulk drug product:4-[4-(methylsulfonyl)phenyl]-3-phenyl-5-hydroxyfuran-2-one; and4-[4-(methylsulfonyl)phenyl]-3-phenyl-2,5-furandione. In someembodiments, the pharmaceutically acceptable formulation as describedhere includes one or more beneficial rofecoxib impurities, such as4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone.

In some embodiments, the highly pure rofecoxib comprises less than about0.1% total impurities. In some embodiments, the highly pure rofecoxibcomprises less than about 0.075% total impurities. In some embodiments,the highly pure rofecoxib comprises less than about 0.050% totalimpurities. In some embodiments, the highly pure rofecoxib comprisesless than about 0.025% total impurities. In some embodiments, the highlypure rofecoxib comprises less than about 0.001% total impurities.

In some embodiments, the highly pure rofecoxib comprises less than about0.10%, 0.05%, 0.02%, or 0.01% of4-[4-(methylsulphonyl)phenyl]-3-phenyl-2,5-furandione. In someembodiments, the highly pure rofecoxib comprises less than about 0.10%,0.05%, 0.02%, or 0.01% of4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In some embodiments,the highly pure rofecoxib comprises less than about 0.10%, 0.05%, 0.02%,or 0.01% of 4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone. In someembodiments, the highly pure rofecoxib comprises less than about 0.10%,0.05%, 0.02%, or 0.01% of4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone.

In some embodiments, the rofecoxib as provided herein contains less thanabout 0.25%, 0.20%, 0.15%, 0.10%, 0.05%, 0.02% or 0.01% of4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone and/or4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone as an impurity. Insome embodiments, the rofecoxib as provided herein contains greater thanor equal to about 0.001%, 0.005%, 0.01%, 0.02%, 0.05%, or 0.10%, but inall cases less than or equal to about 0.15%, of4-[4-(methylthio)phenyl]-3-phenyl-2(5H)-furanone and/or4-[4-(methylsulfinyl)phenyl]-3-phenyl-2(5H)-furanone as an impurity.

Purity of the resulting rofecoxib as described herein is determined as apercent area basis, typically as quantified by analyticalchromatography, such as using HPLC, UHPLC, UPLC or other analyticalmeans in the art. In some embodiments, the rofecoxib or pharmaceuticallyacceptable salt thereof as provided herein is micronized.

Rofecoxib Pharmacokinetics

It was surprisingly and unexpectedly discovered that the bioavailabilityof “VIOXX” was likely lower than 93%, contrary to the FDA-approvedlabel, and that the formulations and methods described herein canachieve a comparable pharmacokinetic profile to the previously available“VIOXX” tablets after a single administration, despite containing 80% orless rofecoxib than the comparable “VIOXX” tablet.

In some embodiments, a 17.5 mg solid dosage formulation of rofecoxibreaches a median time to Cmax plasma concentration in 4 hours or lessfollowing single administration of the formulation to human subjects. Insome embodiments, a 17.5 mg solid dosage formulation of rofecoxibreaches a median time to Cmax plasma concentration in 3 hours or lessfollowing administration. In some embodiments, a 17.5 mg solid dosageformulation of rofecoxib reaches a median time to Cmax plasmaconcentration in 2.5 hours or less following administration. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib reaches amedian time to Cmax plasma concentration in 2 hours or less followingadministration. In some embodiments, a 17.5 mg solid dosage formulationof rofecoxib has a mean Cmax plasma concentration of more than 100ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean Cmax plasma concentration of more than 150 ng/ml,167 ng/ml, or 190 ng/ml. In some embodiments, a 17.5 mg solid dosageformulation of rofecoxib has a mean Cmax plasma concentration of morethan 200 ng/ml. In some embodiments, a 17.5 mg solid dosage formulationof rofecoxib has a mean Cmax plasma concentration of more than 220ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean Cmax plasma concentration of more than 250 ng/ml.In some embodiments, a 17.5 mg solid dosage formulation of rofecoxib hasa mean Cmax plasma concentration of more than 280 ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 1750 h*ng/ml. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib has a mean AUC_(0-∞) of more than2000 h*ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean AUC_(0-∞) of more than 2500 h*ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 3000 h*ng/ml. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib has a mean AUC_(0-∞) of more than3100 h*ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib has a mean AUC_(0-∞) of more than 3500 h*ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 4000 h*ng/ml. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib has a mean AUC_(0-∞) of more than4500 h*ng/ml. In some embodiments, a 17.5 mg solid dosage form ofrofecoxib achieves a mean Cmax plasma concentration within 80% to 125%of 224 ng/ml. In some embodiments, a 17.5 mg solid dosage form ofrofecoxib achieves a mean AUC_(0-∞) within 80% to 125% of 3110 h*ng/ml.In some embodiments, a 17.5 mg solid dosage formulation of rofecoxibreaches a Cmax plasma concentration of least 167 ng/ml, 170 ng/ml, 175ng/ml, 180 ng/ml, or higher following single administration of theformulation to a human subject. In some embodiments, a 17.5 mg soliddosage formulation of rofecoxib reaches an AUC_(0-∞) of at least 2600h*ng/ml, 2750 h*ng/ml, 2900 h*ng/ml, 3050 h*ng/ml, 3100 h*ng/ml, 3200h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml or higher followingsingle administration of the formulation to a human subject.

In certain aspects, the subject matter disclosed herein provides amethod of treating pain, fever, or inflammation in a subject byadministering to the subject a solid dosage formulation comprising 17.5mg of rofecoxib or a pharmaceutically acceptable salt thereof. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib reaches amean Cmax plasma concentration in less than 4 hours following singleadministration of the formulation to human subjects. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib reaches amedian time to Cmax plasma concentration in 3 hours or less followingadministration. In some embodiments, a 17.5 mg solid dosage formulationof rofecoxib reaches a mean Cmax plasma concentration in less than 2.5hours following administration. In some embodiments, a 17.5 mg soliddosage formulation of rofecoxib reaches a mean Cmax plasma concentrationin less than 2 hours following administration. In some embodiments, a17.5 mg solid dosage formulation of rofecoxib has a mean Cmax plasmaconcentration of more than 150 ng/ml, 167 ng/ml, or 190 ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib achieves amean Cmax plasma concentration of more than 200 ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib achieves amean Cmax plasma concentration of more than 220 ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib achieves amean Cmax plasma concentration of more than 250 ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib achieves amean Cmax plasma concentration of more than 280 ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib achieves amean AUC_(0-∞) of more than 1750 h*ng/ml. In In some embodiments, a 17.5mg solid dosage formulation of rofecoxib achieves a mean AUC_(0-∞) ofmore than 2000 h*ng/ml. In some embodiments, a 17.5 mg solid dosageformulation of rofecoxib achieves a mean AUC_(0-∞) of more than 2500h*ng/ml. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib achieves a mean AUC_(0-∞) of more than 3000 h*ng/ml. In someembodiments, a 17.5 mg solid dosage formulation of rofecoxib achieves amean AUC_(0-∞) of more than 3100 h*ng/ml. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib achieves a mean AUC_(0-∞) of morethan 3500 h*ng/ml. In some embodiments, a 17.5 mg solid dosageformulation of rofecoxib achieves a mean Cmax plasma concentration ofmore than 200 ng/ml in less than 3.5 hours following administration withan AUC_(0-∞) of more than 3000 h*ng/ml. In some embodiments, a 17.5 mgsolid dosage formulation of rofecoxib as described herein achieves amean Cmax, Tmax, or AUC_(0-∞) that is bioequivalent to a 25 mg tablet ofVIOXX. In some embodiments, a 17.5 mg solid dosage formulation ofrofecoxib as described herein achieves efficacy in treating pain, fever,or inflammation in a subject that is equal to or greater than a 25 mgtablet of VIOXX. In some embodiments, a 17.5 mg solid dosage form ofrofecoxib achieves a mean Cmax plasma concentration within 80% to 125%of 224 ng/ml. In some embodiments, a 17.5 mg solid dosage form ofrofecoxib achieves a mean AUC_(0-∞) within 80% to 125% of 3110 h*ng/ml.In some embodiments, a 17.5 mg solid dosage formulation of rofecoxibreaches a Cmax plasma concentration of least 167 ng/ml, 170 ng/ml, 175ng/ml, 180 ng/ml, or higher following single administration of theformulation to a human subject. In some embodiments, a 17.5 mg soliddosage formulation of rofecoxib reaches an AUC_(0-∞) of at least 2600h*ng/ml, 2750 h*ng/ml, 2900 h*ng/ml, 3050 h*ng/ml, 3100 h*ng/ml, 3200h*ng/ml, 3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml or higher followingsingle administration of the formulation to a human subject.

In some embodiments, a 20 mg solid dosage formulation of rofecoxibreaches a median time to Cmax plasma concentration in 4 hours or lessfollowing single administration of the formulation to human subjects. Insome embodiments, a 20 mg solid dosage formulation of rofecoxib reachesa median time to Cmax plasma concentration in 3 hours or less followingadministration. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib reaches a median time to Cmax plasma concentration in 2.5hours or less following administration. In some embodiments, a 20 mgsolid dosage formulation of rofecoxib reaches a median time to Cmaxplasma concentration in 2 hours or less following administration. Insome embodiments, a 20 mg solid dosage formulation of rofecoxib has amean Cmax plasma concentration of more than 150 ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 191 ng/ml, 200 ng/ml, 215 ng/ml,or 225 ng/ml. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib has a mean Cmax plasma concentration of more than 250 ng/ml.In some embodiments, a 20 mg solid dosage formulation of rofecoxib has amean Cmax plasma concentration of more than 258 ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 300 ng/ml. In some embodiments, a20 mg solid dosage formulation of rofecoxib has a mean AUC_(0-∞) of morethan 2000 h*ng/ml. In some embodiments, a 20 mg solid dosage formulationof rofecoxib has a mean AUC_(0-∞) of more than 2500 h*ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 3000 h*ng/ml. In some embodiments, a 20 mg soliddosage formulation of rofecoxib has a mean AUC_(0-∞) of more than 3400h*ng/ml. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib has a mean AUC_(0-∞) of more than 3500 h*ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 4000 h*ng/ml. In some embodiments, a 20 mg soliddosage form of rofecoxib achieves a mean Cmax plasma concentrationwithin 80% to 125% of 259 ng/ml. In some embodiments, a 20 mg soliddosage form of rofecoxib achieves a mean AUC_(0-∞) within 80% to 125% of3550 h*ng/ml. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib reaches a Cmax plasma concentration of least 190 ng/ml, 205ng/ml, 220 ng/ml, 235 ng/ml, 250 ng/ml, or higher following singleadministration of the formulation to a human subject. In someembodiments, a 20 mg solid dosage formulation of rofecoxib reaches anAUC_(0-∞) of at least 3000 h*ng/ml, 3200 h*ng/ml, 3350 h*ng/ml, 3500h*ng/ml, 3650 h*ng/ml, 3800 h*ng/ml, 3950 h*ng/ml, or higher followingsingle administration of the formulation to a human subject.

In certain aspects, the subject matter disclosed herein provides amethod of treating pain, fever, or inflammation in a subject byadministering to the subject a solid dosage formulation comprising 20 mgof rofecoxib or a pharmaceutically acceptable salt thereof. In someembodiments, a 20 mg solid dosage formulation of rofecoxib reaches amean Cmax plasma concentration in less than 4 hours following singleadministration of the formulation to human subjects. In someembodiments, a 20 mg solid dosage formulation of rofecoxib reaches amedian time to Cmax plasma concentration 3 hours or less followingadministration. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib reaches a mean Cmax plasma concentration in less than 2.5hours following administration. In some embodiments, a 20 mg soliddosage formulation of rofecoxib reaches a mean Cmax plasma concentrationin less than 2 hours following administration. In some embodiments, a 20mg solid dosage formulation of rofecoxib has a mean Cmax plasmaconcentration of more than 150 ng/ml. In some embodiments, a 20 mg soliddosage formulation of rofecoxib achieves a mean Cmax plasmaconcentration of more than 191 ng/ml, 200 ng/ml, 215 ng/ml, or 225ng/ml. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib achieves a mean Cmax plasma concentration of more than 250ng/ml. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib achieves a mean Cmax plasma concentration of more than 258ng/ml. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib achieves a mean Cmax plasma concentration of more than 300ng/ml. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib achieves a mean AUC_(0-∞) of more than 2000 h*ng/ml. In someembodiments, a 20 mg solid dosage formulation of rofecoxib achieves amean AUC_(0-∞) of more than 2500 h*ng/ml. In some embodiments, a 20 mgsolid dosage formulation of rofecoxib achieves a mean AUC_(0-∞) of morethan 3000 h*ng/ml. In some embodiments, a 20 mg solid dosage formulationof rofecoxib achieves a mean AUC_(0-∞) of more than 3400 h*ng/ml. Insome embodiments, a 20 mg solid dosage formulation of rofecoxib achievesa mean AUC_(0-∞) of more than 3500 h*ng/ml. In some embodiments, a 20 mgsolid dosage formulation of rofecoxib achieves a mean Cmax plasmaconcentration of more than 191 ng/ml, 200 ng/ml, 215 ng/ml, or 225 ng/mlin less than 3.5 hours following administration with an AUC_(0-∞) ofmore than 3000 h*ng/ml. In some embodiments, a 20 mg solid dosageformulation of rofecoxib as described herein achieves a mean Cmax, Tmax,or AUC_(0-∞) that is bioequivalent to a 25 mg tablet of VIOXX. In someembodiments, a 20 mg solid dosage formulation of rofecoxib as describedherein achieves efficacy in treating pain, fever, or inflammation in asubject that is equal to or greater than a 25 mg tablet of VIOXX. Insome embodiments, a 20 mg solid dosage form of rofecoxib achieves a meanCmax plasma concentration within 80% to 125% of 259 ng/ml. In someembodiments, a 20 mg solid dosage form of rofecoxib achieves a meanAUC_(0-∞) within 80% to 125% of 3550 h*ng/ml. In some embodiments, a 20mg solid dosage formulation of rofecoxib reaches a Cmax plasmaconcentration of least 190 ng/ml, 205 ng/ml, 220 ng/ml, 235 ng/ml, 250ng/ml, or higher following single administration of the formulation to ahuman subject. In some embodiments, a 20 mg solid dosage formulation ofrofecoxib reaches an AUC_(0-∞) of at least 3000 h*ng/ml, 3200 h*ng/ml,3350 h*ng/ml, 3500 h*ng/ml, 3650 h*ng/ml, 3800 h*ng/ml, 3950 h*ng/ml, orhigher following single administration of the formulation to a humansubject.

In some embodiments, a 25 mg solid dosage formulation of rofecoxibreaches a mean Cmax plasma concentration in less than 3 hours followingsingle administration of the formulation to human subjects. In someembodiments, a 25 mg solid dosage formulation of rofecoxib reaches amean Cmax plasma concentration in less than 2.5 hours followingadministration. In some embodiments, a 25 mg solid dosage formulation ofrofecoxib reaches a mean Cmax plasma concentration in less than 2 hoursfollowing administration. In some embodiments, a 25 mg solid dosageformulation of rofecoxib has a mean Cmax plasma concentration of morethan 240 ng/ml. In some embodiments, a 25 mg solid dosage formulation ofrofecoxib has a mean Cmax plasma concentration of more than 250 ng/ml.In some embodiments, a 25 mg solid dosage formulation of rofecoxib has amean Cmax plasma concentration of more than 300 ng/ml. In someembodiments, a 25 mg solid dosage formulation of rofecoxib has a meanCmax plasma concentration of more than 320 ng/ml. In some embodiments, a25 mg solid dosage formulation of rofecoxib has a mean AUC_(0-∞) of morethan 4250 h*ng/ml. In some embodiments, a 25 mg solid dosage formulationof rofecoxib has a mean AUC_(0-∞) of more than 4500 h*ng/ml. In someembodiments, a 25 mg solid dosage formulation of rofecoxib has a meanAUC_(0-∞) of more than 4550 h*ng/ml. In some embodiments, a 25 mg soliddosage formulation of rofecoxib has a mean AUC_(0-∞) of more than 4700h*ng/ml. In some embodiments, a 25 mg solid dosage formulation ofrofecoxib reaches a mean Cmax plasma concentration of more than 240ng/ml in a median time of about 3 hours or less following administrationwith an AUC_(0-∞) of more than 4250 h*ng/ml. In some embodiments, a 25mg solid dosage form of rofecoxib achieves a mean Cmax plasmaconcentration within 80% to 125% of 325 ng/ml. In some embodiments, a 25mg solid dosage form of rofecoxib achieves a mean AUC_(0-∞) within 80%to 125% of 4590 h*ng/ml.

In certain aspects, the subject matter disclosed herein provides amethod of treating pain, fever, or inflammation in a subject byadministering to the subject a 25 mg solid dosage formulation ofrofecoxib or a pharmaceutically acceptable salt thereof. In someembodiments, a 25 mg solid dosage formulation of rofecoxib reaches amean Cmax plasma concentration in less than 3 hours followingadministration. In some embodiments, a 25 mg solid dosage formulation ofrofecoxib reaches a mean Cmax plasma concentration in less than 2.5hours following administration. In some embodiments, a 25 mg soliddosage formulation of rofecoxib reaches a mean Cmax plasma concentrationin less than 2 hours following administration. In some embodiments, a 25mg solid dosage formulation of rofecoxib has a mean Cmax plasmaconcentration of more than 240 ng/ml. In some embodiments, a 25 mg soliddosage formulation of rofecoxib achieves a mean Cmax plasmaconcentration of more than 250 ng/ml. In some embodiments, a 25 mg soliddosage formulation of rofecoxib has a mean Cmax plasma concentration ofmore than 300 ng/ml. In some embodiments, a 25 mg solid dosageformulation of rofecoxib achieves a mean Cmax plasma concentration ofmore than 320 ng/ml. In some embodiments, a 25 mg solid dosageformulation of rofecoxib achieves a mean AUC_(0-∞) of more than 4250h*ng/ml. In some embodiments, a 25 mg solid dosage formulation ofrofecoxib achieves a mean AUC_(0-∞) of more than 4500 h*ng/ml. In someembodiments, a 25 mg solid dosage formulation of rofecoxib achieves amean AUC_(0-∞) of more than 4550 h*ng/ml. In some embodiments, a 25 mgsolid dosage formulation of rofecoxib achieves a mean AUC_(0-∞) of morethan 4700 h*ng/ml. In some embodiments, a 25 mg solid dosage formulationof rofecoxib achieves a Cmax plasma concentration of more than 240 ng/mlin about 3 hours following administration with an AUC_(0-∞) of more than4250 h*ng/ml. In some embodiments, a 25 mg solid dosage formulation ofrofecoxib as described herein achieves a mean Cmax, Tmax, or AUC_(0-∞)that is higher than a 25 mg tablet of VIOXX. In some embodiments, a 25mg solid dosage form of rofecoxib achieves a mean Cmax plasmaconcentration within 80% to 125% of 325 ng/ml. In some embodiments, a 25mg solid dosage form of rofecoxib achieves a mean AUC_(0-∞) within 80%to 125% of 4590 h*ng/ml.

In certain aspects, the subject matter disclosed herein provides amethod of treating pain, fever, or inflammation in a subject byadministering to the subject a solid dosage formulation comprising 10 mgto 50 mg of rofecoxib or a pharmaceutically acceptable salt thereof. Insome embodiments, the formulation achieves a mean Cmax plasmaconcentration from 9.8 ng/ml to 16 ng/ml for each 1 mg of rofecoxib inthe formulation. In some embodiments, the formulation achieves a meanCmax plasma concentration from 10 ng/ml to 14 ng/ml for each 1 mg ofrofecoxib in the formulation. In some embodiments, the formulationachieves a mean Cmax plasma concentration from 10 ng/ml to 13 ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, theformulation achieves a mean Cmax plasma concentration from 80% to 125%of 12.8 ng/ml. In some embodiments, the formulation reaches a meanAUC_(0-∞) of 170 h*ng/ml to 235 h*ng/ml for each 1 mg of rofecoxib inthe formulation. In some embodiments, the formulation reaches a meanAUC_(0-∞) of 177 h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib inthe formulation. In some embodiments, the formulation achieves a meanAUC_(0-∞) of 177 h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib inthe formulation. In some embodiments, the formulation achieves a meanAUC_(0-∞) of 180 h*ng/ml to 225 h*ng/ml for each 1 mg of rofecoxib inthe formulation. In some embodiments, the formulation reaches a meanAUC_(0-∞) of 190 h*ng/ml to 215 h*ng/ml for each 1 mg of rofecoxib inthe formulation.

In some embodiments, a method is provided for treating pain, fever, orinflammation in patients within a patient population, the methodcomprising providing a solid dosage formulation comprising 10 mg to 50mg of rofecoxib, more specifically 17.5 mg to 25 mg, to the patientpopulation, wherein the formulation achieves a mean Cmax plasmaconcentration from 9.8 ng/ml to 16 ng/ml for each 1 mg of rofecoxib inthe formulation following single administration of the formulation tothe patients within the patient population. In some embodiments, thesolid dosage formulation of rofecoxib achieves a mean Cmax plasmaconcentration from 10 ng/ml to 14 ng/ml for each 1 mg of rofecoxib inthe formulation. In some embodiments, the solid dosage formulation ofrofecoxib achieves a mean Cmax plasma concentration from 10 ng/ml to 13ng/ml for each 1 mg of rofecoxib in the formulation. In someembodiments, the solid dosage formulation of rofecoxib achieves a meanCmax plasma concentration from 80% to 125% of 12.8 ng/ml. In someembodiments, the solid dosage formulation of rofecoxib reaches a meanAUC_(0-∞) of 170 h*ng/ml to 235 h*ng/ml for each 1 mg of rofecoxib inthe formulation. In some embodiments, the solid dosage formulation ofrofecoxib reaches a mean AUC_(0-∞) of 177 h*ng/ml to 225 h*ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, theformulation achieves a mean AUC_(0-∞) of 177 h*ng/ml to 225 h*ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, theformulation achieves a mean AUC_(0-∞) of 180 h*ng/ml to 225 h*ng/ml foreach 1 mg of rofecoxib in the formulation. In some embodiments, thesolid dosage formulation of rofecoxib reaches a mean AUC_(0-∞) of 190h*ng/ml to 215 h*ng/ml for each 1 mg of rofecoxib in the formulation.

In certain aspects, the subject matter disclosed herein provides amethod of treating pain, fever, or inflammation in a male or femalesubject by administering to the subject a solid dosage formulationcomprising 10 mg to 50 mg of rofecoxib or a pharmaceutically acceptablesalt thereof. In some embodiments, a single administration of a soliddosage formulation comprising 12.5 mg to 25 mg of rofecoxib or apharmaceutically acceptable salt thereof to healthy female subjectsresults in a mean Cmax plasma concentration that is at least 5%, 10%,15%, 20%, 25%, or 30% greater than that resulting from a singleadministration of the same formulation to male subjects. In someembodiments, a single administration of a solid dosage formulationcomprising 12.5 mg to 25 mg of rofecoxib or a pharmaceuticallyacceptable salt thereof to healthy female subjects results in a meanAUC_(0-∞) that is at least 5%, 10%, 15%, 20%, 25%, or 30% greater thanthat resulting from a single administration of the same formulation tomale subjects.

In some embodiments, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a solid dosage formulation of 10 mg to 50 mg of rofecoxib,wherein a single administration of the formulation in Caucasian subjectsless than 65 years of age achieves a mean AUC_(0-∞) that is greater thanthat achieved following a single administration of the formulation toAfrican American subjects less than 65 years of age. In someembodiments, a single administration of a solid dosage formulationcomprising 12.5 mg to 25 mg of rofecoxib or a pharmaceuticallyacceptable salt thereof to Caucasian subjects results in a meanAUC_(0-∞) that is at least 1%, 2%, 5%, 9%, or 10% greater than thatachieved following a single administration of the formulation to AfricanAmerican subjects less than 65 years of age. In some embodiments, theformulation comprises 17.5 mg to 25 mg of rofecoxib. In someembodiments, the formulation comprises 17.5 mg of rofecoxib. In someembodiments, the formulation comprises 20 mg of rofecoxib. In someembodiments, the formulation comprises 25 mg of rofecoxib.

In some embodiments, the subject matter disclosed herein provides amethod for treating pain, fever, or inflammation in a subject byadministering a solid dosage formulation comprising 12.5 mg ofrofecoxib, wherein the formulation achieves a mean plasma concentrationof at least about 0.2 ng/ml, 0.3 ng/ml, 0.4 ng/ml, or 0.5 ng/ml at 15minutes following single administration of the formulation to humansubjects less than 65 years of age. In some embodiments, the subjectmatter disclosed herein provides a method for treating pain, fever, orinflammation in a subject by administering a solid dosage formulationcomprising 12.5 mg of rofecoxib, wherein the formulation achieves anarithmetic mean plasma concentration of at least about 0.8 ng/ml, 0.9ng/ml, or 1.0 ng/ml at 15 minutes following single administration of theformulation to human subjects less than 65 years of age. In someembodiments, the subject matter disclosed herein provides a method fortreating pain, fever, or inflammation in a subject by administering asolid dosage formulation comprising 17.5 mg of rofecoxib, wherein theformulation achieves a mean plasma concentration of at least about 0.3ng/ml, 0.4 ng/ml, 0.5 ng/ml, or 0.6 ng/ml at 15 minutes following singleadministration of the formulation to human subjects less than 65 yearsof age. In some embodiments, the subject matter disclosed hereinprovides a method for treating pain, fever, or inflammation in a subjectby administering a solid dosage formulation comprising 17.5 mg ofrofecoxib, wherein the formulation achieves an arithmetic mean plasmaconcentration of at least about 1.8 ng/ml, 2.0 ng/ml, 2.2 ng/ml, or 2.4ng/ml at 15 minutes following single administration of the formulationto human subjects less than 65 years of age. In some embodiments, thesubject matter disclosed herein provides a method for treating pain,fever, or inflammation in a subject by administering a solid dosageformulation comprising 20 mg of rofecoxib, wherein the formulationachieves a mean plasma concentration of at least about 0.8 ng/ml, 0.9ng/ml, 1.0 ng/ml, 1.1 ng/ml, or 1.16 ng/ml at 15 minutes followingsingle administration of the formulation to human subjects less than 65years of age. In some embodiments, the subject matter disclosed hereinprovides a method for treating pain, fever, or inflammation in a subjectby administering a solid dosage formulation comprising 20 mg ofrofecoxib, wherein the formulation achieves an arithmetic mean plasmaconcentration of at least about 4.6 ng/ml, 5.0 ng/ml, 5.4 ng/ml, or 5.7ng/ml at 15 minutes following single administration of the formulationto human subjects less than 65 years of age. In some embodiments, thesubject matter disclosed herein provides a method for treating pain,fever, or inflammation in a subject by administering a solid dosageformulation comprising 25 mg of rofecoxib, wherein the formulationachieves a mean plasma concentration of at least about 1.0 ng/ml, 1.1ng/ml, 1.2 ng/ml, or 1.3 ng/ml at 15 minutes following singleadministration of the formulation to human subjects less than 65 yearsof age. In some embodiments, the subject matter disclosed hereinprovides a method for treating pain, fever, or inflammation in a subjectby administering a solid dosage formulation comprising 25 mg ofrofecoxib, wherein the formulation achieves an arithmetic mean plasmaconcentration of at least about 4.6 ng/ml, 5.0 ng/ml, 5.4 ng/ml, or 5.6ng/ml at 15 minutes following single administration of the formulationto human subjects less than 65 years of age. In some embodiments, thesubject matter disclosed herein provides a method for treating pain,fever, or inflammation in a subject by administering a solid dosageformulation comprising 12.5 mg of rofecoxib, wherein the formulationachieves a mean plasma concentration of at least about 27 ng/ml, 29ng/ml, 31 ng/ml, or 33 ng/ml at 45 minutes following singleadministration of the formulation to human subjects less than 65 yearsof age. In some embodiments, the subject matter disclosed hereinprovides a method for treating pain, fever, or inflammation in a subjectby administering a solid dosage formulation comprising 12.5 mg ofrofecoxib, wherein the formulation achieves an arithmetic mean plasmaconcentration of at least about 45 ng/ml, 48 ng/ml, 51 ng/ml, 54 ng/ml,or 56 ng/ml at 45 minutes following single administration of theformulation to human subjects less than 65 years of age. In someembodiments, the subject matter disclosed herein provides a method fortreating pain, fever, or inflammation in a subject by administering asolid dosage formulation comprising 17.5 mg of rofecoxib, wherein theformulation achieves a mean plasma concentration of at least about 45ng/ml, 47 ng/ml, 49 ng/ml, or 51 ng/ml at 45 minutes following singleadministration of the formulation to human subjects less than 65 yearsof age. In some embodiments, the subject matter disclosed hereinprovides a method for treating pain, fever, or inflammation in a subjectby administering a solid dosage formulation comprising 17.5 mg ofrofecoxib, wherein the formulation achieves an arithmetic mean plasmaconcentration of at least about 74 ng/ml, 79 ng/ml, 84 ng/ml, 89 ng/ml,or 93 ng/ml at 45 minutes following single administration of theformulation to human subjects less than 65 years of age. In someembodiments, the subject matter disclosed herein provides a method fortreating pain, fever, or inflammation in a subject by administering asolid dosage formulation comprising 20 mg of rofecoxib, wherein theformulation achieves a mean plasma concentration of at least about 58ng/ml, 62 ng/ml, 66 ng/ml, 70 ng/ml, or 72 ng/ml at 45 minutes followingsingle administration of the formulation to human subjects less than 65years of age. In some embodiments, the subject matter disclosed hereinprovides a method for treating pain, fever, or inflammation in a subjectby administering a solid dosage formulation comprising 20 mg ofrofecoxib, wherein the formulation achieves an arithmetic mean plasmaconcentration of at least about 112 ng/ml, 116 ng/ml, or 121 ng/ml at 45minutes following single administration of the formulation to humansubjects less than 65 years of age. In some embodiments, the subjectmatter disclosed herein provides a method for treating pain, fever, orinflammation in a subject by administering a solid dosage formulationcomprising 25 mg of rofecoxib, wherein the formulation achieves a meanplasma concentration of at least about 78 ng/ml, 85 ng/ml, 92 ng/ml, or97 ng/ml, at 45 minutes following single administration of theformulation to human subjects less than 65 years of age. In someembodiments, the subject matter disclosed herein provides a method fortreating pain, fever, or inflammation in a subject by administering asolid dosage formulation comprising 25 mg of rofecoxib, wherein theformulation achieves an arithmetic mean plasma concentration of at leastabout 133 ng/ml, 139 ng/ml, 145 ng/ml, 151 ng/ml, or 159 ng/ml at 45minutes following single administration of the formulation to humansubjects less than 65 years of age.

Specific Compositions

In some embodiments, the subject matter discloses a drug productincluding an immediate-release tablet that contains either 12.5-, 17.5-,20-, or 25-mg rofecoxib. In some embodiments, the tablets are 7.2-mm indiameter tablets. In some embodiments, the tablets are off-white tolight yellow, round, and uncoated with no markings. In some embodiments,rofecoxib tablets disclosed herein are for oral administration. In someembodiments, the drug product does not comprise a liquisolid, orallydisintegrating tablet, rapid dissolving tablets, or chewable.

In some embodiments, each rofecoxib tablet for oral administrationcontains either 12.5-, 17.5-, 20-, or 25-mg of rofecoxib. In someembodiments, each rofecoxib tablet also contains one or more of thefollowing inactive ingredients: croscarmellose sodium, hydroxypropylcellulose, lactose, magnesium stearate, microcrystalline cellulose, andpigment blend yellow. The quantitative composition of one embodiment ofthe 25-mg tablet and the function and compendial status of eachcomponent are listed in FIG. 1.

In some embodiments, the pigment blend is comprised of three compendialmaterials as listed in Table 4 below.

TABLE 4 Components of the Pigment Blend Components Reference toStandards^(a) Titanium dioxide USP-NF, Ph. Eur. Iron oxide yellow USP-NFIron oxide red USP-NF USP = United States Pharmacopeia; NF = NationalFormulary; Ph. Eur. = European Pharmacopeia ^(a)When referred to aPharmacopeia, the current edition of this Pharmacopeia is applied.

Exemplary excipients used in the manufacture of rofecoxib are listed inTable 5 below. Water is used only as a granulation medium.

TABLE 5 Excipients for Rofecoxib Tablets Excipient Compendial ReferenceCroscarmellose sodium USP-NF, Ph. Eur., JP HydroxypropylcelluloseUSP-NF, Ph. Eur., JP Lactose monohydrate USP-NF, Ph. Eur., JP Magnesiumstearate USP-NF, Ph. Eur., JP Microcrystalline cellulose USP-NF, Ph.Eur., JP Pigment blend yellow Water USP-NF, Ph. Eur. USP = United StatesPharmacopeia; NF = National Formulary; Ph. Eur. = European Pharmacopeia;JP = Japanese Pharmacopeia.

Tables 6A and 6B compare exemplary embodiments of the composition ofeach tablet dose strength. In some embodiments, the tablet weight is 200mg for each dose strength. In some embodiments, tablet dose strengthsare manufactured by varying the quantities of the first threecomponents, while maintaining the 1:1 ratio of microcrystallinecellulose to lactose monohydrate.

TABLE 6A Composition of Rofecoxib Tablets 25-mg Tablet 20-mg Tablet17.5-mg Tablet 12.5-mg Tablet % % % % (w/w) (w/w) (w/w) (w/w) per mg perper mg per per mg per per mg per Components tablet tablet tablet tablettablet tablet tablet tablet Intragranular Rofecoxib^(a) 12.50 25.0 10.0020.0 8.75 17.5 6.25 12.5 Lactose monohydrate 39.85 79.7 41.10 82.241.725 83.45 42.975 85.95 Microcrystalline cellulose 39.85 79.7 41.1082.2 41.725 83.45 42.975 85.95 Hydroxypropylcellulose 3.00 6.0 3.00 6.003.00 6.0 3.00 6.0 Croscarmellose sodium 2.00 4.0 2.00 4.0 2.00 4.0 2.004.0 Water NA^(b) NA^(b) NA^(b) NA^(b) NA^(b) NA^(b) NA^(b) NA^(b)Extragranular Pigment blend yellow 0.30 0.6 0.30 0.6 0.30 0.6 0.30 0.6Croscarmellose sodium 2.00 4.0 2.00 4.0 2.00 4.0 2.00 4.0 Magnesiumstearate 0.50 1.0 0.50 1.0 0.50 1.0 0.50 1.0 Totals 100.00 200.0 100.00200.0 100.00 200.0 100.00 200.0 ^(a)Note that the amount of rofecoxibmay be adjusted for purity and moisture content. An adjustment will bemade to the amounts of lactose monohydrate and microcrystallinecellulose used to maintain tablet weight. ^(b)Water for granulation isremoved upon drying of the wet mass.

TABLE 6B Composition of Rofecoxib Tablets Manufactured by Process B₂25-mg Tablet 20-mg Tablet 17.5-mg Tablet 12.5-mg Tablet % (w/w) % (w/w)% (w/w) % (w/w) per mg per per mg per per mg per per mg per Componentstablet tablet tablet tablet tablet tablet tablet tablet IntragranularRofecoxib^(a) 12.50 25.0 10.00 20.0 8.75 17.5 6.25 12.5 Lactosemonohydrate 39.85 79.7 41.10 82.2 41.725 83.45 42.975 85.95Microcrystalline cellulose 39.85 79.7 41.10 82.2 41.725 83.45 42.97585.95 Hydroxypropylcellulose 3.00 6.0 3.00 6.00 3.00 6.0 3.00 6.0Croscarmellose sodium 2.00 4.0 2.00 4.0 2.00 4.0 2.00 4.0 Water NA^(b)NA^(b) NA^(b) NA^(b) NA^(b) NA^(b) NA^(b) NA^(b) Pigment blend yellow0.30 0.6 0.30 0.6 0.30 0.6 0.30 0.6 Extragranular Croscarmellose sodium2.00 4.0 2.00 4.0 2.00 4.0 2.00 4.0 Magnesium stearate 0.50 1.0 0.50 1.00.50 1.0 0.50 1.0 Totals 100.00 200.0 100.00 200.0 100.00 200.0 100.00200.0 ^(a)Note that the amount of rofecoxib may be adjusted for purityand moisture content. An adjustment will be made to the amounts oflactose monohydrate and microcrystalline cellulose used to maintaintablet weight. ^(b)Water for granulation is removed upon drying of thewet mass.

In some embodiments, rofecoxib is a single crystal form (Form A), theonly structure reported in the Cambridge Structural Database (Groom C R,Bruno M P, Lightfoot S C, et al. The Cambridge Structural Database. ActaCryst. 2016; B72:171-179. (Entry CAXMUJ:https://www.ccdc.cam.ac.uk/structures/Search?Compound=Rofecoxib&DatabaseToSearch=Published).Rofecoxib is practically insoluble in water (solubility <0.1 mg/mL).Rofecoxib has no ionizable moieties and cannot form salts; thesolubility of rofecoxib cannot be increased by changing pH. Therefore,in some embodiments, rofecoxib is micronized in the final step of themanufacturing process in order to increase dissolution rate.

Description of Manufacturing Process and Process Controls for RofecoxibTablets

The specific process used to manufacture rofecoxib granules andsubsequent rofecoxib tablets is Process B1, which is described below andillustrated in FIG. 1. The process nomenclature consists of a letterwith a subscripted number. The letter is indexed when a major change ismade to the process during development; the subscripted number isindexed when a minor change is made.

Exemplary Preparation of Rofecoxib Granules:

Step 1G: Blend lactose monohydrate and rofecoxib.

Step 2G: Pass the lactose-rofecoxib blend, microcrystalline cellulose,hydroxypropylcellulose, and croscarmellose sodium through anappropriate-sized sieve screen as the granulator is charged.

Step 3G: Mix the dry powder in the high-shear granulator.

Step 4G: Spray the water of granulation onto the contents of thehigh-shear granulator while mixing. The target amount of water ofgranulation is 32% relative to the mass of the dry powder in thegranulator. The actual amount of water added may vary.

Step 5G: Discharge the wet granules from the granulator into ahigh-speed mill equipped with an appropriate-sized screen. Mill the wetgranules.

Step 6G: Dry the wet-milled granules into a fluid-bed drier.

Step 7G: Mill the dried granules using a high-speed mill equipped withan appropriate-sized screen.

Exemplary Preparation of Rofecoxib Tablets:

Step 1T: Blend croscarmellose sodium and pigment.

Step 2T: Pass the rofecoxib granules, croscarmellose sodium-pigmentblend, and magnesium stearate through an appropriate-sized sieve screenas the blender is charged. Note more than one granulation batch may beused in this step.

Step 3T: Blend the powders.

Step 4T: Compress the blended powder into tablets.

Step 5T: Dedust and metal check the tablets. FIGS. 13A-B show flowdiagrams for rofecoxib tablet manufacturing Process B₁.

In some embodiments, e.g. the formation of those tablets described inTable 6B, the pigment may be added in preparation of the rofecoxibgranules prior to formation of the tablets.

Disintegrants and Dissolution Rate

Disintegrants included in tablet or granulate formulations are auxiliaryagents which can promote the disintegration of said tablets orgranulates upon contact with liquids and bodily fluids. Disintegrantsare essential excipients in solid formulations because they can lead toenhanced dissolution of tablets into coarse fragments and further intosmaller particles. Disintegrants ultimately result in the activeingredients of solid drug formulations interacting sufficiently withliquids or bodily fluids and forming a solution. In general, highertablet densities are associated with poorer solubility profiles.Therefore, the addition of disintegrants into tablets promotes theirdesired rapid dissolution, or disintegration and dissolution. In someembodiments, the formulation described herein further includes agranular component and an extragranular component, wherein the granularcomponent includes an intragranular component including the rofecoxiband one or more disintegrants, and wherein the extragranular componentincludes one or more disintegrants. In some embodiments, the rofecoxibin the formulation has a d90 particle size from about 10-12 μm, a d50particle size from about 3-4 μm, and a d10 particle size from about0.5-1.0 μm.

In some embodiments of the pharmaceutically acceptable formulationdescribed herein, the one or more disintegrants in the granularcomponent of the formulation may include starches, clays, celluloses,algins, gums, cross-linked polymers, croscarmellose, croscarmellosesodium, crospovidone, sodium starch glycolate, and combinations thereof.In some embodiments, the one or more disintegrants in the granularcomponent are about 0.5% (w/w) about 1% (w/w), about 2% (w/w), about 3%(w/w), about 4% (w/w), about 5% (w/w), about 6% (w/w), about 7% (w/w),about 8% (w/w), about 9% (w/w), or about 10% (w/w) of the formulation.

In some embodiments of the pharmaceutically acceptable formulationdescribed herein, the one or more disintegrants in the extragranularcomponent may include starches, clays, celluloses, algins, gums,cross-linked polymers, croscarmellose, croscarmellose sodium,crospovidone, sodium starch glycolate, and combinations thereof. In someembodiments, the one or more disintegrants in the extragranularcomponent are about 0.5% (w/w), about 1% (w/w), about 2% (w/w), about 3%(w/w), about 4% (w/w), about 5% (w/w), about 6% (w/w), about 7% (w/w),about 8% (w/w), about 9% (w/w), about 10% (w/w) of the formulation.

In some embodiments, the disintegrant in the granular component and thedisintegrant in the extragranular component are together about 1% (w/w),about 2% (w/w), about 3% (w/w), about 4% (w/w), about 5% (w/w), about 6%(w/w), about 7% (w/w), about 8% (w/w), about 9% (w/w), about 10% (w/w),about 11% (w/w), about 12% (w/w), about 13% (w/w), about 14% (w/w),about 15% (w/w) of the formulation.

The dissolution rate of a solid formulation such as an oral tabletrefers to the proportion of drug which enters a solution in a givenamount of time. In some embodiments of the pharmaceutically acceptableformulations described herein, the oral tablet provides a dissolutionrate of at least about 70%, at least about 75%, at least about 80%, atleast about 85%, at least about 90%, at least about 95%, at least about100% of the rofecoxib or pharmaceutically acceptable salt thereof byabout 15 minutes.

In some embodiments, the dissolution rate is measured in about 1% SDS ata paddle speed of about 40 rpm, about 45 rpm, about 50 rpm, about 55rpm, about 60 rpm, about 65 rpm, about 70 rpm, about 75 rpm, about 80rpm, about 85 rpm, about 90 rpm, about 95 rpm and at a temperature ofabout 37.0° C.±0.5° C. In some embodiments, the dissolution rate ismeasured in about 1.5% SDS at a paddle speed of about 40 rpm, about 45rpm, about 50 rpm, about 55 rpm, about 60 rpm, about 65 rpm, about 70rpm, about 75 rpm, about 80 rpm, about 85 rpm, about 90 rpm, about 95rpm and at a temperature of about 37.0° C.±0.5° C. In some embodiments,the dissolution rate is measured in about 2% SDS at a paddle speed ofabout 40 rpm, about 45 rpm, about 50 rpm, about 55 rpm, about 60 rpm,about 65 rpm, about 70 rpm, about 75 rpm, about 80 rpm, about 85 rpm,about 90 rpm, about 95 rpm and at a temperature of about 37.0° C.±0.5°C. In some embodiments, the dissolution rate is measured using a USPType II apparatus. In some embodiments, the dissolution rate is measuredwith a USP Type II apparatus using 900 mL of 2% SDS, a paddle speed of50 rpm, and a temperature of 37.0° C.±0.5°.

In some embodiments, the ratio of granular disintegrant to extragranulardisintegrant is about 40% (w/w) to about 60% (w/w). In some embodiments,the ratio of granular disintegrant to extragranular disintegrant isabout 45% (w/w) to about 55% (w/w). In some embodiments, the ratio ofgranular disintegrant to extragranular disintegrant is about 50% (w/w)to about 50% (w/w). In some embodiments, the ratio of granulardisintegrant to extragranular disintegrant is about 55% (w/w) to about45% (w/w). In some embodiments, the ratio of granular disintegrant toextragranular disintegrant is about 60% (w/w) to about 40% (w/w).

Granulation Process and Granules for Oral Formulations

Granulation is the process of forming of granules from powders or solidsubstances, producing a material which has the consistency or granules.This process is highly used in the pharmaceutical industry to producetablets for oral administration of drugs. The process of granulationgenerally refers to the agglomeration of very fine particles into largergranules. The size of the produced granules depends on their intendedsubsequent use and can vary largely from 20 μm to 4 mm.

In the course of a granulation process, particles from one or morepowder substances can be combined to form a granule. Bonds can be formedbetween these particles in the process of granulation by compression orby using a binding agent. Subsequently, this allows for tablets orpellets to be formed within specific pre-determined limits.

In some embodiments of the pharmaceutically acceptable formulationdescribed herein, the rofecoxib or pharmaceutically acceptable saltthereof is formulated into granules and at least about 20%, at leastabout 25%, at least about 35%, or at least about 40% of the granules areless than about 75 μm. In some embodiments, the rofecoxib orpharmaceutically acceptable salt thereof is formulated into granules andat least about 40%, at least about 45%, at least about 50%, at leastabout 55%, or at least about 60% of the granules are less than about 150μm. In some embodiments, the rofecoxib or pharmaceutically acceptablesalt thereof is formulated into granules and at least about 60%, atleast about 65%, at least about 70%, at least about 75%, or at leastabout 80% of the granules are less than about 250 μm. In someembodiments, the rofecoxib or pharmaceutically acceptable salt thereofis formulated into granules and at least about 70%, at least about 75%,at least about 80%, at least about 85%, or at least about 90% of thegranules are less than about 425 μm. In some embodiments, the rofecoxibor pharmaceutically acceptable salt thereof is formulated into granulesand at least about 80%, at least about 85%, at least about 90%, at leastabout 95%, or at least about 100% of the granules are less than about1000 μm. Prior to being formulated into granules, the rofecoxib orpharmaceutically acceptable salt thereof may be micronized. In someembodiments, the particle size distribution of the rofecoxib or apharmaceutically acceptable salt thereof used in the formulation is asfollows: a) the d90 particle size is less than about 12 μm, 11 μm, 10μm, 9 μm, 8 μm, 7 μm, 6 μm, 5 μm, or 4 μm; b) the d50 particle size isless than about 4 μm, 3 μm, 2 μm, or 1 μm; and c) the d10 particle sizeis less than about 1 μm, 0.9 μm, 0.8 μm, 0.7 μm, 0.6 μm, or 0.5 μm. Insome embodiments, the particle size distribution of the rofecoxib or apharmaceutically acceptable salt thereof used in the formulation is asfollows: a) the d90 particle size is about 10-12 μm; b) the d50 particlesize is about 3-4 μm; and c) the d10 particle size is about 0.5-1.0 μm.

Additional Components

The pharmaceutically acceptable formulations presented herein canfurther comprise one or more additional components selected from a widevariety of excipients known in the pharmaceutical formulation art.According to the desired properties of the tablet or capsule, any numberof ingredients can be selected, alone or in combination, based upontheir known uses in preparing the compositions of the present invention.

Diluents

Diluents function as fillers in solid formulations such as tablets.Fillers increase weight and improve content uniformity of the solidformulations. In some embodiments of the pharmaceutically acceptableformulations described herein, at least a portion of one or morediluents is in the granular component. The one or more diluents includedicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin,mannitol, dry starch, powdered sugar, sorbitol, sucrose, inositol,monohydrate, microcrystalline cellulose, and combinations thereof.

In some embodiments, the lactose monohydrate diluent is about 25% (w/w),30% (w/w), about 32% (w/w), about 34% (w/w), about 35% (w/w), about 37%(w/w), about 39% (w/w), about 40% (w/w), about 42% (w/w), about 44%(w/w) about 45% (w/w), about 47% (w/w), about 49% (w/w), or about 50%(w/w) of the formulation. In some embodiments, the microcrystallinecellulose diluent is about 30% (w/w), about 32% (w/w), about 34% (w/w),about 35% (w/w), about 37% (w/w), about 39% (w/w), about 40% (w/w),about 42% (w/w), about 44% (w/w), about 45% (w/w), about 47% (w/w),about 49% (w/w), or about 50% (w/w) of the formulation. In someembodiments, the diluent is about 70% (w/w), about 72% (w/w), about 74%(w/w), about 75% (w/w), about 77% (w/w), about 79% (w/w), about 80%(w/w), about 82% (w/w), about 84% (w/w), about 85% (w/w), about 87%(w/w), or about 89% (w/w) of the formulation.

Binders

Binders can be used in the formulation of solid oral dosage forms tohold the active pharmaceutical ingredient and inactive ingredientstogether in a cohesive mix. In some embodiments, at least a portion ofthe binder is in the granular component. In some embodiments, the one ormore binder include starches, gelatins, sugars, gums, waxes, water,alcohols, celluloses, acacia gum, tragacanth, corn starch, methylcellulose, panwar gum, ghatti gum, mucilage of isapol husks,carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, sucrose,glucose, dextrose, molasses, lactose, hydroxypropyl cellulose, andcombinations thereof. In some embodiments, the binder is about 0.5%(w/w), about 1% (w/w), about 1.5% (w/w), about 2% (w/w), about 2.5%(w/w), about 3% (w/w), about 3.5% (w/w), about 4% (w/w) about 4.5%(w/w), about 5% (w/w), about 5.5% (w/w), about 6% (w/w) of theformulation.

Color Agents

One of the most important reasons for adding coloring agents to solidoral formulations is to prevent errors and confusion for patientsbetween different medications. In some embodiments, at least a portionof the one or more coloring agent is in the extragranular component. Theone or more coloring agents can include pigment blend yellow. In someembodiments, the coloring agent is about 0.20% (w/w), about 0.25% (w/w)about 0.30% (w/w), about 0.35% (w/w), about 0.40% (w/w), about 0.45%(w/w), about 0.50% (w/w), about 0.55% (w/w), about 0.60% (w/w), about0.65% (w/w), or about 0.70% (w/w) of the formulation.

Lubricants

In some embodiments, at least a portion of the lubricant is in theextragranular component. In some embodiments, the one or more lubricantsinclude talc, magnesium stearate, calcium stearate, stearic acid,metallic stearate, hydrogenated vegetable oils, and polyethylene glycol,corn starch, boric acids, sodium chloride, sodium lauryl sulphate,magnesium stearate, and any combination thereof. In some embodiments,the lubricant is about 0.05% (w/w), about 0.10% (w/w), about 0.20%(w/w), about 0.30% (w/w), about 0.40% (w/w), about 0.50% (w/w), about0.60% (w/w), about 0.70% (w/w), about 0.80% (w/w), about 0.90% (w/w),about 1% (w/w), or about 1.2% (w/w), or about 2% (w/w), or about 3%(w/w) of the formulation.

Formulation

In certain aspects, the pharmaceutically acceptable formulation asprovided herein can be formulated as a pharmaceutically acceptable saltor solvate thereof. In some embodiments, the pharmaceutically acceptableformulations as provided herein comprising highly pure rofecoxib or apharmaceutically acceptable salt or solvate thereof as provided hereinmay include the excipients, and may otherwise be formulated, asdescribed in U.S. Pat. No. 6,063,811, which is incorporated herein byreference in its entirety, including but not limited to the formulationsspecified in Examples 2, 2a, 2b, and 2c of U.S. Pat. No. 6,063,811. Theterm “pharmaceutically acceptable salt,” as used herein, refers to therelatively non-toxic, inorganic and organic acid salts of compounds ofthe subject matter described herein. These salts can be prepared in situduring the final isolation and purification of the compounds of thesubject matter described herein, or by separately reacting a purifiedcompound of the subject matter described herein in its free base formwith a suitable organic or inorganic acid, and isolating the salt thusformed. Representative salts include hydrobromide, hydrochloride,sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate,palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate,citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate,glucoheptonate, lactobionate, and laurylsulphonate salts, and the like.See, for example, Berge et al., (1977) “Pharmaceutical Salts”, J. Pharm.Sci. 66:1-19.

The pharmaceutically acceptable salts of the compounds disclosed hereininclude but are not limited to the conventional nontoxic salts orquaternary ammonium salts of the compounds, e.g., from non-toxic organicor inorganic acids. For example, such conventional nontoxic saltsinclude those derived from inorganic acids such as hydrochloride,hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; andthe salts prepared from organic acids such as acetic, butionic,succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic,palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.

In some embodiments, the compounds of the subject matter describedherein may contain one or more acidic functional groups and, thus, arecapable of forming pharmaceutically acceptable salts withpharmaceutically acceptable bases. The term “pharmaceutically-acceptablesalts” in these instances refers to the relatively non-toxic, inorganicand organic base addition salts of compounds of the subject matterdescribed herein. These salts can likewise be prepared in situ duringthe final isolation and purification of the compounds, or by separatelyreacting the purified compound in its free acid form with a suitablebase, such as the hydroxide, carbonate or bicarbonate of apharmaceutically-acceptable metal cation, with ammonia, or with apharmaceutically-acceptable organic primary, secondary, or tertiaryamine. Representative alkali or alkaline earth salts include thelithium, sodium, potassium, calcium, magnesium, and aluminum salts, andthe like. Representative organic amines useful for the formation of baseaddition salts include ethylamine, diethylamine, ethylenediamine,ethanolamine, diethanolamine, piperazine, and the like. See, forexample, Berge et al., supra.

Formulations of the subject matter described herein include but are notlimited to those suitable for oral administration. The formulations mayconveniently be presented in unit dosage form and may be prepared by anymethods well known in the art of pharmacy. The amount of activeingredient which can be combined with a carrier or excipient material toproduce a single dosage form will vary depending upon the host beingtreated and the particular mode of administration. The amount of activeingredient, which can be combined with a carrier or excipient materialto produce a single dosage form will generally be that amount of thecompound which produces a therapeutic effect. Generally, out of 100%,this amount will range from about 1% to about 99% of active ingredient,preferably from about 5% to about 70%, most preferably from about 10% toabout 30%.

Methods of preparing these pharmaceutically acceptable formulations orcompositions include the step of bringing into association a compound ofthe subject matter described herein with the carrier or excipient and,optionally, one or more accessory ingredients. In general, theformulations are prepared by uniformly and intimately bringing intoassociation a compound of the subject matter described herein withliquid carriers or excipients, or finely divided solid carriers orexcipient, or both, and then, if necessary, shaping the product.

Formulations of the subject matter described herein suitable for oraladministration may be in the form of capsules, cachets, pills, tablets,lozenges (using a flavored basis, usually sucrose and acacia ortragacanth), powders, granules, or as a solution or a suspension in anaqueous or non-aqueous liquid, or as an oil-in-water or water-in-oilliquid emulsion, or as an elixir or syrup, or as pastilles (using aninert base, such as gelatin and glycerin, or sucrose and acacia), and/oras mouthwashes and the like, each containing a predetermined amount of acompound of the subject matter described herein as an active ingredient.A compound of the subject matter described herein may also beadministered as a bolus, electuary or paste.

In solid dosage forms of the subject matter described herein for oraladministration (capsules, tablets, pills, dragees, powders, granules,and the like), the active ingredient is mixed with one or morepharmaceutically acceptable carriers or excipients, such as sodiumcitrate or dicalcium phosphate, and/or any of the following: fillers orextenders, such as starches, lactose, sucrose, glucose, mannitol, and/orsilicic acid; binders, such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinyl pyrrolidone, sucrose, and/or acacia;humectants, such as glycerol; disintegrating agents, such as agar-agar,calcium carbonate, potato or tapioca starch, alginic acid, certainsilicates, sodium carbonate, and sodium starch glycolate; solutionretarding agents, such as paraffin; absorption accelerators, such asquaternary ammonium compounds; wetting agents, such as, for example,sodium lauryl sulfate, sodium dodecyl sulfate, cetyl alcohol, glycerolmonostearate, and polyethylene oxide-polybutylene oxide copolymer;absorbents, such as kaolin and bentonite clay; lubricants, such as talc,calcium stearate, magnesium stearate, solid polyethylene glycols, sodiumlauryl sulfate, and mixtures thereof; and coloring agents. In the caseof capsules, tablets and pills, the pharmaceutically acceptableformulation may also comprise buffering agents. Solid pharmaceuticallyacceptable formulation of a similar type may also be employed as fillersin soft and hard-filled gelatin capsules using such excipients aslactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients or excipients. Compressed tablets may beprepared using binder (for example, gelatin or hydroxybutylmethylcellulose), lubricant, inert diluent, preservative, disintegrant (forexample, sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface-active or dispersing agent. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticallyacceptable formulation of the subject matter described herein, such asdragees, capsules, pills, and granules, may optionally be scored orprepared with coatings and shells, such as enteric coatings and othercoatings well known in the pharmaceutical-formulating art. They may alsobe formulated so as to provide slow or controlled release of the activeingredient therein using, for example, hydroxybutylmethyl cellulose invarying proportions, to provide the desired release profile, otherpolymer matrices, liposomes, and/or microspheres. They may be sterilizedby, for example, filtration through a bacteria-retaining filter, or byincorporating sterilizing agents in the form of sterile solidformulations, which can be dissolved in sterile water or some othersterile injectable medium immediately before use. These formulations mayalso optionally contain opacifying agents and may be of a formulationthat they release the active ingredient(s) only, or preferentially, in acertain portion of the gastrointestinal tract, optionally, in a delayedmanner. Examples of embedding formulations, which can be used includepolymeric substances and waxes. The active ingredient can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-described excipients.

Liquid dosage forms for oral administration of the compounds of thesubject matter disclosed herein include pharmaceutically-acceptableemulsions, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to the active ingredient, the liquid dosage forms maycontain inert diluents commonly used in the art, such as, for example,water or other solvents, solubilizing agents and emulsifiers, such asethyl alcohol, isobutyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, butylene glycol, 1,3-butylene glycol, oils (inparticular, cottonseed, groundnut, corn, germ, olive, castor and sesameoils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Additionally,cyclodextrins, e.g., hydroxypropyl-β-cyclodextrin orsulfobutylether-β-cyclodextrin, may be used to solubilize compounds.

Besides inert diluents, the oral formulations can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming, and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar, and tragacanth, and mixtures thereof.

When the compounds of the subject matter disclosed herein areadministered as pharmaceuticals, to humans and animals, they can begiven per se or as a pharmaceutically acceptable formulation containing,for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of activeingredient in combination with a pharmaceutically-acceptable carrier.

The compounds and pharmaceutically acceptable formulation of the subjectmatter disclosed herein can be employed in combination therapies, thatis, the compounds and pharmaceutically acceptable formulation can beadministered concurrently with, prior to, or subsequent to, one or moreother desired therapeutics or medical procedures. The particularcombination of therapies (therapeutics or procedures) to employ in acombination regimen will take into account compatibility of the desiredtherapeutics and/or procedures and the desired therapeutic effect to beachieved. It will also be appreciated that the therapies employed mayachieve a desired effect for the same disorder (for example, thecompound of the subject matter disclosed herein may be administeredconcurrently with another anticancer agents).

In some embodiments, the compounds of the subject matter disclosedherein may be used to treat arthritic conditions in mammals (e.g.,humans, livestock, and domestic animals), race horses, birds, lizards,and any other organism which can tolerate the compounds.

The subject matter disclosed herein also provides a pharmaceutical packor kit comprising one or more containers filled with one or more of theingredients of the pharmaceutically acceptable formulation of thesubject matter disclosed herein. Optionally associated with suchcontainer(s) can be a notice in the form prescribed by a governmentalagency regulating the manufacture, use, or sale of pharmaceuticals orbiological products, which notice reflects approval by the agency ofmanufacture, use, or sale for human administration.

Wetting agents, emulsifiers, and lubricants, such as sodium laurylsulfate, magnesium stearate, and polyethylene oxide-polybutylene oxidecopolymer, as well as coloring agents, release agents, coating agents,sweetening, flavoring and perfuming agents, preservatives, andantioxidants can also be present in the pharmaceutically acceptableformulation described herein.

In one embodiment, the pharmaceutically acceptable formulation usefulaccording to the methods of the subject matter described herein can beformulated in any manner suitable for pharmaceutical use.

In one embodiment, the formulations of the subject matter disclosedherein can be administered in pharmaceutically acceptable solutions,which may routinely contain pharmaceutically acceptable concentrationsof salt, buffering agents, preservatives, compatible carriers,adjuvants, excipients and optionally other therapeutic ingredients.

Administration

Some aspects of the subject matter disclosed herein involveadministering an effective amount of a pharmaceutically acceptableformulation to a subject to achieve a specific outcome.

For use in therapy, an effective amount of the compound can beadministered to a subject by any mode allowing the compound to be takenup by the appropriate target cells. “Administering” the pharmaceuticalacceptable formulation of the subject matter described herein can beaccomplished by any means known to the skilled artisan.

The concentration of compounds included in formulations used in themethods of the subject matter disclosed herein can range from about 1 nMto about 100 μM. Effective doses are believed to range from about 10picomole/kg to about 100 micromole/kg.

The pharmaceutically acceptable formulation disclosed herein can beprepared and administered in dose units. Solid dose units are tablets,capsules, powders, and suppositories. For treatment of a patient,different doses may be necessary depending on activity of the compound,manner of administration, purpose of the administration (i.e.,prophylactic or therapeutic), nature and severity of the disorder, ageand body weight of the patient. The administration of a given dose canbe carried out both by single administration in the form of anindividual dose unit or else several smaller dose units. Repeated andmultiple administration of doses at specific intervals of days, weeks,or months apart are also contemplated by the subject matter describedherein.

The pharmaceutically acceptable formulation described herein can beadministered per se (neat) or in the form of apharmaceutically-acceptable salt. When used in medicine the salts shouldbe pharmaceutically acceptable, but non-pharmaceutically-acceptablesalts can conveniently be used to prepare pharmaceutically-acceptablesalts thereof. Such salts include, but are not limited to, thoseprepared from the following acids: hydrochloric, hydrobromic, sulphuric,nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulphonic,tartaric, citric, methane sulphonic, formic, malonic, succinic,naphthalene-2-sulphonic, and benzene sulphonic. Also, such salts can beprepared as alkaline metal or alkaline earth salts, such as sodium,potassium or calcium salts of the carboxylic acid group.

The compounds useful in the subject matter disclosed herein can bedelivered in mixtures of more than two such compounds. A mixture canfurther include one or more adjuvants in addition to the combination ofcompounds.

A variety of administration routes may be available. The particular modeselected will depend, of course, upon the particular compound selected,the age and general health status of the subject, the particularcondition being treated, and the dosage required for therapeuticefficacy. The methods of the subject matter described herein, generallyspeaking, can be practiced using any mode of administration that ismedically acceptable, meaning any mode that produces effective levels ofresponse without causing clinically unacceptable adverse effects.Preferred modes of administration are discussed above.

The formulations can conveniently be presented in unit dosage form andcan be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the compounds into associationwith a carrier which constitutes one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing the compounds into association with a liquid carrier, a finelydivided solid carrier, or both, and then, if necessary, shaping theproduct.

Other delivery systems can include time-release, delayed release, orsustained-release delivery systems. Such systems can avoid repeatedadministrations of the compounds, increasing convenience to the subjectand the physician. Many types of release delivery systems are availableand known to those of ordinary skill in the art. They include polymerbase systems such as poly(lactide-glycolide), copolyoxalates,polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyricacid, and polyanhydrides. Microcapsules of the foregoing polymerscontaining drugs are described in, for example, U.S. Pat. No. 5,075,109.Delivery systems also include non-polymer systems that are: lipidsincluding sterols such as cholesterol, cholesterol esters and fattyacids, or neutral fats such as mono-di- and tri-glycerides; hydrogelrelease systems; silastic systems; peptide based systems; wax coatings;compressed tablets using conventional binders and excipients; partiallyfused implants; and the like. Specific examples include, but are notlimited to: (a) erosional systems in which an agent of the subjectmatter described herein is contained in a form within a matrix such asthose described in U.S. Pat. Nos. 4,452,775, 4,675,189, and 5,736,152,and (b) diffusional systems in which an active component permeates at acontrolled rate from a polymer such as described in U.S. Pat. Nos.3,854,480, 5,133,974 and 5,407,686.

In one aspect, the pharmaceutically acceptable formulation of rofecoxibas provided herein can be administered in a variety of manners,including without limitation, orally. The form in which the drug will beadministered (e.g., tablet, capsule, solution, suspension, emulsion)will depend on the route by which it is administered. In one aspect, thesubject matter disclosed herein includes a pharmaceutically acceptableformulation comprising substantially pure or highly pure rofecoxib asprovided herein and a pharmaceutically acceptable carrier, wherein thepharmaceutically acceptable formulation is in the form of a tablet, andwherein the amount of the rofecoxib as provided herein is 10 mg, 10.5mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 20 mg, 21 mg, 22 mg, 22.5 mg, or 25mg. In another aspect, the subject matter disclosed herein includes apharmaceutically acceptable formulation comprising substantially pure orhighly pure rofecoxib as provided herein and a pharmaceuticallyacceptable carrier or excipient, wherein the pharmaceutically acceptableformulation is in the form of a tablet, and wherein the amount of therofecoxib as provided herein is about 1 mg, 2 mg, 3 mg, 5 mg, 6.25 mg,7.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 20 mg, 21 mg, 22mg, 22.5 mg, 25 mg, 50 mg, 60 mg, or 70 mg.

In another aspect, the subject matter disclosed herein includes apharmaceutically acceptable formulation comprising substantially pure orhighly pure rofecoxib as provided herein and a pharmaceuticallyacceptable carrier or excipient, wherein the pharmaceutically acceptableformulation is in the form of a tablet, and wherein the amount of therofecoxib as provided herein is about 0.10 mg/kg, 0.15 mg/kg, 0.20mg/kg, 0.25 mg/kg, 0.30 mg/kg, 0.35 mg/kg, 0.40 mg/kg, 0.45 mg/kg, 0.50mg/kg, 0.55 mg/kg, 0.60 mg/kg, 0.65 mg/kg, or 0.70 mg/kg.

In one aspect, the pharmaceutically acceptable formulation comprisingrofecoxib as provided herein may be packaged with a set of instructionswarning the patient of cardiovascular and/or gastrointestinal risksassociated with administration of the formulation.

The formulations, both for human medical use and veterinary use, ofcompounds according to the subject matter described herein typicallyinclude such compounds in association with a pharmaceutically acceptablecarrier.

As used herein, the phrase “pharmaceutically-acceptable carrier”includes but is not limited to a pharmaceutically-acceptable material,formulation or vehicle, such as a solid filler, diluent, excipient, orencapsulating material, involved in carrying or transporting the subjectpharmaceutical agent from one organ, or portion of the body, to anotherorgan, or portion of the body. Each carrier must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand not injurious to the patient. Some examples of materials which canserve as pharmaceutically-acceptable carriers include: sugars, such aslactose, glucose, and sucrose; starches, such as corn starch and potatostarch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth;malt; gelatin; and talc; excipients, such as cocoa butter andsuppository waxes. The term “carrier” denotes an organic or inorganicingredient, natural or synthetic, with which the active ingredient iscombined to facilitate the application. The components of thepharmaceutically acceptable formulation also are capable of beingcomingled with the compounds of the present subject matter, and witheach other, in a manner such that there is no interaction which wouldsubstantially impair the desired pharmaceutical efficiency.

The carrier should be “acceptable” in the sense of being compatible withcompounds of the subject matter described herein and not deleterious tothe recipient. Pharmaceutically acceptable carriers, in this regard, areintended to include any and all solvents, dispersion media, coatings,absorption delaying agents, and the like, compatible with pharmaceuticaladministration. The use of such media and agents for pharmaceuticallyactive substances is known in the art. Except insofar as anyconventional media or agent is incompatible with the active compound,use thereof in the formulations is contemplated. Supplementary activecompounds (identified or designed according to the subject matterdisclosed herein and/or known in the art) also can be incorporated intothe formulations. The formulations can conveniently be presented indosage unit form and can be prepared by any of the methods well known inthe art of pharmacy. In general, some formulations are prepared bybringing the compound into association with a liquid carrier or a finelydivided solid carrier or both, and then, if necessary, shaping theproduct into the desired formulation. A pharmaceutically acceptableformulation of the subject matter disclosed herein should be formulatedto be compatible with its intended route of administration. Solutions orsuspensions can include the following components: a sterile diluent suchas water, saline solution, fixed oils, polyethylene glycols, glycerine,propylene glycol or other synthetic solvents; antibacterial agents suchas benzyl alcohol or methyl parabens; antioxidants such as ascorbic acidor sodium bisulfite; chelating agents such as ethylenediaminetetraaceticacid; buffers such as acetates, citrates or phosphates and agents forthe adjustment of tonicity such as sodium chloride or dextrose. The pHcan be adjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide.

Useful solutions for oral administration can be prepared by any of themethods well known in the pharmaceutical art, described, for example, inRemington's Pharmaceutical Sciences, 18th ed. (Mack Publishing Company,1990). Formulations of the subject matter described herein suitable fororal administration can be in the form of: discrete units such ascapsules, gelatin capsules, sachets, tablets, troches, or lozenges, eachcontaining a predetermined amount of the drug; a powder or granularformulation; a solution or a suspension in an aqueous liquid ornon-aqueous liquid; or an oil-in-water emulsion or a water-in-oilemulsion. A tablet can be made by compressing or molding the drugoptionally with one or more accessory ingredients. Compressed tabletscan be prepared by compressing, in a suitable machine, the drug in afree-flowing form such as a powder or granules, optionally mixed by abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets can be made by molding, in a suitable machine, a mixtureof the powdered drug and suitable carrier moistened with an inert liquiddiluent.

Oral formulations generally include an inert diluent or an ediblecarrier. For the purpose of oral therapeutic administration, the activecompound can be incorporated with excipients. Oral formulation preparedusing a fluid carrier for use as a mouthwash include the compound in thefluid carrier and are applied orally and swished and expectorated orswallowed. Pharmaceutically compatible binding agents, and/or adjuvantmaterials can be included as part of the formulation. The tablets,pills, capsules, troches and the like can contain any of the followingingredients, or compounds of a similar nature: a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an excipient suchas starch or lactose; a disintegrating agent such as alginic acid,Primogel, or corn starch; a lubricant such as magnesium stearate orSterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring.

Oral formulations can be formulated in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form refers tophysically discrete units suited as unitary dosages for the subject tobe treated; each unit containing a predetermined quantity of activecompound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the subject matter disclosed herein aredictated by and directly dependent on the unique characteristics of theactive compound and the therapeutic effect to be achieved, and thelimitations inherent in the art of compounding such an active compoundfor the treatment of individuals.

Methods of Use

A pharmaceutically acceptable formulation comprising substantially pureor highly pure rofecoxib as presented herein may be used in thetreatment or prevention of conditions or diseases in humans.

In one aspect, the subject matter disclosed herein includesadministering a pharmaceutically acceptable formulation comprisingrofecoxib having a favorable impurity profile to a subject to treat orprevent a disease or condition, including but not limited to one of thefollowing: osteoarthritis, rheumatoid arthritis, analgesia, systemicjuvenile idiopathic arthritis, migraine or headaches, juvenilerheumatoid arthritis, ankylosing spondylitis, acute pain, and primarydysmenorrhea. In another aspect, the disease or condition isfibromyalgia.

In another aspect, the disease or condition is lower back pain (e.g.chronic lower back pain). In another aspect, the disease or condition ispsoriatic arthritis.

In other aspects, the disease or condition is pain-associated with acondition caused by a bleeding disorder, including migraine associatedwith von Willebrand deficiency. In another aspect, a patient receivingtreatment for migraine associated with von Willebrand deficiencyexpresses von Willebrand factor at a level about 50% below normal.

In one aspect, the treatment described herein may be administered to asubject of any age. In another aspect, the patient is age 2 or older, orage 12 years or older. In another aspect, the patient is of age 12 to 75years old, inclusive.

In one aspect, the subject is a healthy human subject. In anotheraspect, the subject is screened for all or certain of the study protocolinclusion or exclusion criteria described below as part of thetreatment.

In another aspect, the subject is within a patient population that has areduced risk of arterial thrombosis, cardiovascular thrombotic events,or other serious cardiovascular disease or events, for example humanswith inherited bleeding disorders or coagulopathies such as hemophiliaor von Willebrand disease, or humans with medically-induced bleedingdisorders or coagulopathies.

In one aspect, the subject is screened for a history or current symptomsof cardiovascular disease. In one aspect, if the patient is determinedto have a history or current symptoms of cardiovascular disease, thepatient is not administered the pharmaceutically acceptable formulation.In another aspect, if it is determined that the patient does not have ahistory or current symptoms of cardiovascular disease, the patient isadministered the pharmaceutically acceptable formulation as further setforth herein. In yet another aspect, the patient is screened for one ormore risk factors that would increase the likelihood of the patienthaving a serious cardiovascular thrombotic event followingadministration of the pharmaceutically acceptable formulation as furtherset forth herein. In one aspect, if it is determined that the patientmay be safely administered the pharmaceutically acceptable formulationas further set forth herein without increasing the likelihood of thepatient having a serious cardiovascular thrombotic event, then thepatient is administered the pharmaceutically acceptable formulation asfurther set forth herein.

In another aspect, the subject is screened for a history or currentsymptoms of gastrointestinal bleeding, ulceration, and perforation. Inone aspect, if the patient is determined to have a history or currentsymptoms of gastrointestinal bleeding, ulceration, and perforation, thepatient is not administered the pharmaceutically acceptable formulation.In another aspect, if it is determined that the patient does not have ahistory or current symptoms of gastrointestinal bleeding, ulceration,and perforation, the patient is administered the pharmaceuticallyacceptable formulation as further set forth herein.

The subject may be screened for a history or current symptoms of bothcardiovascular disease or gastrointestinal bleeding, ulceration, andperforation, in addition to any of the study protocol inclusion orexclusion criteria listed below.

A pharmaceutically acceptable formulation comprising rofecoxib that isadministered for any of the diseases or conditions described herein maybe substantially pure or highly pure, or may be essentially free of, orfree of, one or more of impurities.

In another aspect, a pharmaceutically acceptable formulation comprisingrofecoxib as provided herein is administered to a subject who has mild,moderate, or severe pain or inflammation associated with a conditioncaused by a bleeding disorder. Pain may be measured through anyclinically-validated pain assessment measure. In one aspect, pain ismeasured through the Pain Intensity Numerical Rating Scale. In anotheraspect, pain associated with a specific condition caused by a bleedingdisorder, hemophilic arthropathy, is measured through the Pain IntensityNumerical Rating Scale or the Patient Assessment of Arthropathy Pain(Visual Analog Scale; VAS).

In one aspect, a pharmaceutically acceptable formulation comprisingrofecoxib as provided herein is administered to a subject who has painassociated SJIA. In another aspect, a pharmaceutically acceptableformulation comprising rofecoxib as provided herein is administered to asubject who has migraine associated with von Willebrand deficiency,wherein the subject receiving treatment expresses von Willebrand factorat a level about 50% below normal.

In one aspect, the treatment of the subject matter disclosed hereinincludes administration of a pharmaceutically acceptable formulationcomprising about 10 mg of rofecoxib as provided herein per day. In oneaspect, the treatment of the subject matter disclosed herein includesadministration of a pharmaceutically acceptable formulation comprisingabout 10.5 mg of rofecoxib as provided herein per day. In one aspect,the treatment of the subject matter disclosed herein includesadministration of a pharmaceutically acceptable formulation comprisingabout 11 mg of rofecoxib as provided herein per day. In one aspect, thetreatment of the subject matter disclosed herein includes administrationof a pharmaceutically acceptable formulation comprising about 11.5 mg ofrofecoxib as provided herein per day. In one aspect, the treatment ofthe subject matter disclosed herein includes administration of apharmaceutically acceptable formulation comprising about 12 mg ofrofecoxib as provided herein per day. In one aspect, the treatment ofthe subject matter disclosed herein includes administration of apharmaceutically acceptable formulation comprising about 12.5 mg ofrofecoxib as provided herein per day. In one aspect, the treatment ofthe subject matter disclosed herein includes administration of apharmaceutically acceptable formulation comprising about 20 mg ofrofecoxib as provided herein per day. In one aspect, the treatment ofthe subject matter disclosed herein includes administration of apharmaceutically acceptable formulation comprising about 21 mg ofrofecoxib as provided herein per day. In one aspect, the treatment ofthe subject matter disclosed herein includes administration of apharmaceutically acceptable formulation comprising about 22 mg ofrofecoxib as provided herein per day. In one aspect, the treatment ofthe subject matter disclosed herein includes administration of apharmaceutically acceptable formulation comprising about 22.5 mg ofrofecoxib as provided herein per day. In another aspect, the treatmentincludes the administration of a pharmaceutically acceptable formulationcomprising about 25 mg of rofecoxib as provided herein per day. In oneaspect, the treatment of the subject matter disclosed herein includesadministration of a pharmaceutically acceptable formulation comprisingabout 50 mg of rofecoxib as provided herein per day. In another aspect,the treatment includes the administration of a pharmaceuticallyacceptable formulation comprising about 1 mg, 2 mg, 3 mg, 5 mg, 6.25 mg,7.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 17.5 mg, 20 mg,21 mg, 21.5 mg, 22.5 mg, 25 mg, 50 mg, 60 mg, or 70 mg of rofecoxib asprovided herein per day. Treatment may be administered once daily in theform of one or more tablets. In other aspects, the pharmaceuticallyacceptable formulation comprising rofecoxib as provided herein isadministered two times or more daily.

In one aspect, a treatment regimen is provided for the safe treatment ofpain, inflammation, migraine and/or arthritis. The pain, inflammation,migraine and/or arthritis may be associated with a disease or conditioncaused by a bleeding disorder. In one aspect, the treatment subject is ahuman patient of any age. In another aspect, the patient is age 12 yearsor older.

The treatment regimen may comprise the administration of an initial (orfirst) dose of a pharmaceutically acceptable formulation comprising 4mg, 8 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 17.5 mg, 20mg, or 25 mg of rofecoxib once daily as further described herein. Thetreatment regimen may further comprise evaluating the subject afteradministration of the initial dose to determine if the initial dose wasfully, partially, or not effective at treating the pain, inflammation,migraine and/or arthritis. In another aspect, the treatment regimen maycomprise determining if the subject could benefit from theadministration of a higher dose of rofecoxib. The evaluation anddetermining steps may take place after a single administration of theinitial dose (e.g. two days, three days, one week, two weeks, or longerafter the first administration of the initial dose), or after multipleadministrations of the initial dose, and may be performed by aphysician, physician's assistant, nurse, or other health care provider.In one aspect, the evaluation and determination steps may be based onsubject-reported outcomes, and may include an assessment of the benefitof a higher dose of rofecoxib compared to any potential safety risksassociated with that higher dose. For example, if a subject experiencesa clinically meaningful decrease in pain after administration of theinitial dose, it may be determined that the subject should continue onthe initial dose through the duration of the bleeding episode thatcaused the pain.

The treatment regimen may further comprise the administration of asubsequent (or second) dose of a pharmaceutically acceptable formulationcomprising 10 mg, 12.5 mg, 17.5 mg, 20 mg, 21 mg, 22 mg, 22.5 mg, 25 mg,30 mg, 35 mg, 40 mg, 45 mg, or 50 mg of rofecoxib once daily if it wasdetermined that the initial dose was not effective or only partiallyeffective at treating the pain, inflammation, migraine and/or arthritis,or if it is determined that the subject could benefit from a higherdaily dose of rofecoxib to treat the pain, inflammation, migraine and/orarthritis (e.g. that a higher dose could achieve a greater reduction inpain in the human). In one aspect, the subsequent dose is administeredif it is determined that the initial dose did not achieve a clinicallymeaningful reduction in pain, inflammation, migraine and/or arthritis inthe human. In another aspect, the subsequent dose is administered if itis determined that the subsequent dose may increase the effectiveness ofthe treatment without increasing the risk of adverse events or otherside effects. In another aspect, a higher dose is not administered if itis determined that the initial dose was effective at treating the pain,inflammation, migraine and/or arthritis. In another aspect, a higherdose is not administered if it is determined that the higher dose wouldincrease the risk of adverse events or other side effects in thesubject. In another aspect, a higher dose is not administered if it isdetermined that the risk of administering the higher dose (e.g. in termsof adverse events or side effects) outweigh the benefits (e.g. in termsof effectiveness of treating the pain, inflammation, migraine and/orarthritis). In another aspect, the step of not administering a higherdose comprises instructing the subject not to take a higher dose of thepharmaceutical composition (e.g. not to take 12.5 mg of thepharmaceutical composition more than once daily).

In one aspect, the treatment includes the administration ofpharmaceutically acceptable formulation comprising about 0.10 mg/kg,0.15 mg/kg, 0.20 mg/kg, 0.25 mg/kg, 0.30 mg/kg, 0.35 mg/kg, 0.40 mg/kg,0.45 mg/kg, 0.50 mg/kg, 0.55 mg/kg, 0.60 mg/kg, 0.65 mg/kg, or 0.70mg/kg.

In one aspect, an effective amount of rofecoxib as provided herein fortreating pain associated with a disease or condition caused by ableeding disorder is about 12.5 mg once daily, and, in another aspects,results fewer side effects or in a reduction of pain equal to or betterthan the use of a pharmaceutically acceptable formulation comprisingabout 25 mg rofecoxib that is not substantially pure or highly pure, oressentially free of, or free of, one or more of the impurities describedherein that was present in previously available rofecoxib bulk drugproduct. In one aspect, an effective amount of rofecoxib as providedherein for treating pain associated with a disease or condition causedby a bleeding disorder is about 1 mg, 2 mg, 3 mg, 5 mg, 6.25 mg, 7.5 mg,10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 17.5 mg, 20 mg, 21 mg,22 mg, 22.5 mg, 25 mg, 50 mg, 60 mg, or 70 mg once daily. As a result, asubject may not need to be administered the higher quantity of activeingredient in order to experience a reduction in pain.

In one aspect, an effective amount rofecoxib as provided herein fortreating pain associated with a disease or condition caused by ableeding disorder, pain associated with systemic juvenile idiopathicarthritis, or migraine associated with von Willebrand deficiency isabout 0.10 mg/kg, 0.15 mg/kg, 0.20 mg/kg, 0.25 mg/kg, 0.30 mg/kg, 0.35mg/kg, 0.40 mg/kg, 0.45 mg/kg, 0.50 mg/kg, 0.55 mg/kg, 0.60 mg/kg, 0.65mg/kg, or 0.70 mg/kg.

In one aspect, the treatment described herein is effective at treatingmild, moderate, or severe pain in a subject without theco-administration of another pain medication or analgesic.

In another aspect, the treatment described herein results in the subjectdecreasing or discontinuing the use of another pain medication oranalgesic, including rescue medications, during the course of thetreatment when compared to before the initiation of the treatment. Inyet another aspect, the treatment results in the subject decreasing ordiscontinuing the use of acetaminophen and/or opioid medications duringthe treatment during the course of the treatment when compared to beforethe initiation of the treatment.

In one aspect, a pharmaceutically acceptable formulation comprisingrofecoxib as provided herein is co-administered with factor replacementtherapy to a subject having a bleeding disorder. In another aspect, thetreatment described herein is administered to a subject having ableeding disorder who is being administered or is taking factorreplacement therapy prophylactically. In one aspect, the apharmaceutically acceptable formulation comprising 10 mg, 10.5 mg, 11mg, 11.5 mg, 12 mg, 12.5 mg, 17.5 mg, 20 mg, 21 mg, 22 mg, 22.5 mg, or25 mg rofecoxib as provided herein is administered once daily to asubject who is also being administered or is taking factor replacementtherapy prophylactically.

In one aspect, a pharmaceutically acceptable formulation comprisingrofecoxib as provided herein is administered daily and does not increaserisk of cardiovascular diseases and/or gastrointestinal bleeding,ulceration, or perforation during the course of the treatment, asdetermined at 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, 52 weeks,and/or two or more years. In another aspect, the rofecoxib as providedherein may be administered during the course of the treatment withoutthe use or co-administration of a gastro-protective agent including butnot limited to an antacid therapy, an H2 antagonist, a proton pumpinhibitor, or misoprostol.

In another aspect, a pharmaceutically acceptable formulation comprisingrofecoxib as provided herein is administered only on an as-needed basis,for example when a subject experiences a pain “flare” described as anincrease in pain rating of >1 or a pain rating of ≥4 to ≤9 based on thePain Intensity Numerical Rating Scale. In yet another aspect, thepharmaceutically acceptable formulation comprising rofecoxib as furtherset forth herein is not administered as a maintenance therapy,prophylactically, or for long term use (e.g., >1 year). In one aspect, apharmaceutically acceptable formulation comprising rofecoxib as providedherein is administered only on an as-needed basis and for short termuse, for example, less than one week, two weeks, three weeks, or fourweeks, or until the pain, migraine, arthritis, inflammation, or otherconditions or symptoms subside or resolve, for example, until there is aclinically significant improvement in pain rating based on the based onthe Pain Intensity Numerical Rating Scale.

In another aspect, the subject uses or is co-administered agastro-protective agent during the course of treatment with apharmaceutically acceptable formulation comprising rofecoxib as providedherein, which prevents or treats gastrointestinal bleeding, ulceration,and perforation in the subject.

In one aspect, the treatment described herein achieves a reduction in atleast 1 from baseline in the Pain Intensity Numerical Rating Scale. Inanother aspect, the treatment described herein achieves a reduction inat least 2, 3, 4, or 5 from baseline in the Pain Intensity NumericalRating Scale.

In one aspect, the reduction in the Pain Intensity Numerical RatingScale is achieved within 1, 2, 3, 4, 5, or 6 days, or 1 week, or 2 weeksof first administering the pharmaceutically acceptable formulation.

In one aspect, the treatment of a disease or condition by theadministering of a pharmaceutically acceptable formulation comprisingsubstantially pure or highly pure rofecoxib does not result in one ormore of the following adverse events: upper respiratory infection,headache, nausea, vomiting, and cough, or one or more of the followingserious adverse events: hemorrhage and hypotension. In one aspect, thetreatment of a disease or condition caused by a bleeding disorder by theadministering of a pharmaceutically acceptable formulation comprisingsubstantially pure or highly pure rofecoxib does not result in anincreased number of joint bleeding events. In another aspect, thetreatment of a disease or condition caused by a bleeding disorder by theadministering of a pharmaceutically acceptable formulation comprisingsubstantially pure or highly pure rofecoxib does not increase the riskof joint bleeding events. In one aspect, the treatment of a disease orcondition caused by a bleeding disorder by the administering of apharmaceutically acceptable formulation comprising substantially pure orhighly pure rofecoxib does not result in an increase in the amount offactor use in the subject. In another aspect, the treatment of a diseaseor condition by the administering of a pharmaceutically acceptableformulation comprising substantially pure or highly pure rofecoxib doesnot result in an increased risk of side effects (including but notlimited to hemorrhaging, hypotension or serious cardiovascularthrombotic events) compared to the previously marketed “VIOXX” productwhen used in that disease or condition. In another aspect, apharmaceutically acceptable formulation comprising substantially pure orhighly pure rofecoxib as provided herein results in greater efficacy ina disease or condition compared to the previously marketed “VIOXX”product when used in that disease or condition (as measured by aclinically-validated measure, such as the Pain Intensity NumericalRating Scale).

In another aspect, the treatment of a disease or condition by theadministering of a pharmaceutically acceptable formulation comprisinghighly pure rofecoxib that is essentially free of, or free of,4-[4-(methylsulfonyl)phenyl]-3-phenyl-5-hydroxyfuran-2-one and/or4-[4-(methylsulfonyl)phenyl]-3-phenyl-2,5-furandione does not result inone or more of the following adverse events: upper respiratoryinfection, headache, nausea, vomiting, and cough, or one or more of thefollowing serious adverse events: hemorrhage and hypotension. In anotheraspect, a pharmaceutically acceptable formulation comprising highly purerofecoxib that is essentially free of, or free of,4-[4-(methylsulfonyl)phenyl]-3-phenyl-5-hydroxyfuran-2-one and/or4-[4-(methylsulfonyl)phenyl]-3-phenyl-2,5-furandione as provided hereinresults in greater efficacy in a disease or condition, or reduced sideeffects (e.g. hemorrhaging, hypotension or serious cardiovascularthrombotic events) compared to the previously marketed “VIOXX” productwhen used in that disease or condition (as measured by aclinically-validated measure, such as the Pain Intensity NumericalRating Scale). The purity of the resulting rofecoxib described as hereinis determined as a percent area basis, typically as quantified byanalytical chromatography, such as using HPLC, UHPLC, UPLC or otheranalytical means in the art.

EXAMPLES Example 1

In some embodiments, the pharmaceutically acceptable formulationdescribed herein relates to a tablet formulation as shown in Table 7below:

TABLE 7 Formulation Percent (w/w) Intragranular Rofecoxib API LactoseMonohydrate, NF, EP, JP, Fastflo 316 SDM Microcrystalline Cellulose, NF,EP, JP Avicel PH 101 Hydroxypropylcellulose, NF, EP, JP, Klucel EXFPurified Water, USP, EP Extragranular Croscarmellose Sodium, NF, EP, JP,(Ac-Di-Sol SD711) Pigment Blend Yellow (HTS: 3206492000) MagnesiumStearate, NF, EP, JP, Hyqual Vegetable Source 2257 Total

In some embodiments the water addition and spray rate in the granulationprocess of the pharmaceutically acceptable formulations as describedhere are as shown in Table 8 below:

TABLE 8 B18079 B18080 B18084 B18085 Parameter (Batch 1) (Batch 2) (Batch3) (Batch 4) Water Addition (%) Spray Rate (g/min)

FIG. 14 shows the granule size distribution across batches. In someembodiments, the granule size distribution is W<75 (34-52% w/w) andW<150 (64-82% w/w).

FIGS. 15A-B show initial dissolution rates for 25 mg rofecoxib tablets.FIG. 15A shows dissolution of 25 mg rofecoxib tablets in 0.1N HCl forbatches 1 and 2. FIG. 15B shows dissolution of 25 mg rofecoxib tabletsin at least 2% SDS for batches 1 and 2. The paddle speed is 75 rpm andthe number of tablets dissolved is 3 per batch.

FIGS. 16A-B show initial dissolution rates for 25 mg rofecoxib tablets.FIG. 16A shows dissolution of 25 mg rofecoxib tablets in 0.1N HCl forbatches 3 and 4. FIG. 16B shows dissolution of 25 mg rofecoxib tabletsin at least 2% SDS for batches 3 and 4. The paddle speed is 75 rpm andthe number of tablets dissolved is 3 per batch.

FIG. 17 shows dissolution of 25 mg rofecoxib tablet as a function ofpercent water added.

Example 2

In some embodiments, the pharmaceutically acceptable formulationdescribed herein relates to a tablet formulation as shown in Table 9below:

TABLE 9 Tablet Formulations Percent (w/w) Batches Batches Batches 1-45-6 6-7 (4 + 0) (2 + 2) (4 + 4) Intragranular Rofecoxib API 12.50 12.5012.50 Lactose Monohydrate, NF, EP, 39.85 39.70 37.70 JP, Fastflo 316 SDMMicrocrystalline Cellulose, NF, 39.85 39.70 37.70 EP, JP Avicel PH101Hydroxypropylcellulose, NF, EP, 3.00 3.00 3.00 JP, Klucel EXFCroscarmellose Sodium, NF, EP, 0.00 2.00 4.00 JP, (Ac-Di-Sol SD711)Purified Water, USP, EP NA NA NA Extragranular Croscarmellose Sodium,NF, EP, 4.00 2.00 4.00 JP, (Ac-Di-Sol SD711) Pigment Blend Yellow (HTS:0.30 0.60 0.60 3206492000) Magnesium Stearate, NF, EP, JP, 0.50 0.500.50 Hyqual Vegetable Source 2257 Total 100.00 100.00 100.00

In some embodiments the water addition, spray rate, and disintegrant inthe granulation process of the pharmaceutically acceptable formulationsas described herein are as shown in Table 10 below:

TABLE 10 Water Addition, Spray Rate, and Disintegrant B18090 B18091B18092 B18093 Parameter (Batch 5) (Batch 6) (Batch 7) (Batch 8) WaterAddition (%) Spray Rate (g/min) Disint

FIG. 18 shows the granule size distribution across batches.

FIGS. 19A-B show dissolution rates for 25 mg rofecoxib tablets. FIG. 19Ashows dissolution of 25 mg rofecoxib tablets in at least 2% SDS forbatches 5 and 6. FIG. 19B shows dissolution of 25 mg rofecoxib tabletsin at least 2% SDS for batches 7 and 8. The paddle speed is 75 rpm andthe number of tablets dissolved is 3 per batch.

FIGS. 20A-B show dissolution rates for 25 mg rofecoxib tablets. FIG. 20Ashows dissolution of 25 mg rofecoxib tablets in at least 2% SDS forbatches 5 and 6 at 75 rpm paddle speed. FIG. 20B shows dissolution of 25mg rofecoxib tablets in at least 2% SDS for batches 5 and 6 at 50 rpmpaddle speed. The number of tablets dissolved is 3 per batch.

All batches have 0.6% extragranular pigment. Two batches use 26% waterduring granulation. Batch 5 has 4% total disintegrant: 2% intragranularand 2% extragranular disintegrant. Batch 7 had 8% total disintegrant: 4%intragranular and 4% extragranular disintegrant.

Two batches will use 32% water during granulation. Batch 6 had 4% totaldisintegrant: 2% intragranular and 2% extragranular disintegrant. Batch8 had 8% total disintegrant: 4% intragranular and 4% extragranulardisintegrant.

100% Dissolution in 15 minutes is observed for Batches 5-8 at 75% rpmpaddle speed. Previous maximum was 86% dissolved in 15 minutes. Based onthe dissolution results and the manufacturing engineering data, there isno advantage to have 8% disintegrant in the formulation. Additionally,decreasing the paddle speed to 50 rpm leads to a slightly lower %dissolved (95% LC) at 15 minutes for Batches 5 and 6.

Example 3

There was no difference in dissolution profile of the two lead 25 mgrofecoxib tablet formulations in 1, 1.5, and 2% SDS at either 50 or 75rpm paddle speed. All media and paddle speeds provided acceptableprofiles. A conservative approach to the dissolution profile is advisedat this stage of development:

-   -   Medium: 1.5 or 2% SDS    -   Paddle speed: 50 rpm

Eight batches of 25-mg rofecoxib tablets were manufactured. Amount ofwater added during granulation is the most critical parameter:

-   -   Water amount affects granule size    -   Low water does not make granules    -   Excess water affects tablet properties (hardness, friability,        disintegration, dissolution)    -   Water content in the 26-32% range yields acceptable tablet        properties

Disintegrant location affects dissolution properties in at least 2% SDS.Extragranular disintegrant (4%) only does not result in completedissolution. Intragranular and extragranular disintegrant result incomplete dissolution. No advantage to 8% total disintegrant over 4%total disintegrant when half is intragranular. Decreasing the paddlespeed to 50 rpm from 75 rpm led to a slightly lower % rofecoxibdissolved at 15 minutes in at least 2% SDS.

In some embodiments, the pharmaceutically acceptable formulationdescribed herein relates to a tablet formulation as shown in Table 11below:

TABLE 11 A Tablet Formulation Percent (w/w) Batches Batches Batches 1-45-6 6-7 Intragranular (4 + 0) (2 + 2) (4 + 4) Rofecoxib API 12.50 12.5012.50 Lactose Monohydrate, NF, EP, 39.85 39.70 37.70 JP, Fastflo 316 SDMMicrocrystalline Cellulose, NF, 39.85 39.70 37.70 EP, JP Avicel PH101Hydroxypropylcellulose, NF, EP, 3.00 3.00 3.00 JP, Klucel EXFCroscarmellose Sodium, NF, EP, 0.00 2.00 4.00 JP, (Ac-Di-Sol SD711)Purified Water, USP, EP NA NA NA Extragranular Croscarmellose Sodium,NF, EP, 4.00 2.00 4.00 JP, (Ac-Di-Sol SD711) Pigment Blend Yellow (HTS:0.30 0.60 0.60 3206492000) Magnesium Stearate, NF, EP, JP, 0.50 0.500.50 Hyqual Vegetable Source 2257 Total 100.00 100.00 100.00

In some embodiments the water addition, spray rate, and disintegrant inthe granulation process of the pharmaceutically acceptable formulationsas described herein as shown in Table 12 below:

TABLE 12 Water, Spray Rate, and Disintegrant B18090 B18091 B18092 B18093Parameter (Batch 5) (Batch 6) (Batch 7) (Batch 8) Water Addition (%)Spray Rate (g/min) Disint

FIG. 21 shows the granule size distribution across batches.

FIGS. 22A-B show dissolution rates for 25 mg rofecoxib tablets. FIG. 22Ashows dissolution of 25 mg rofecoxib tablets in at least 2% SDS forbatches 5 and 6 at 75 rpm paddle speed. FIG. 22B shows dissolution of 25mg rofecoxib tablets in at least 2% SDS for batches 5 and 6 at 50 rpmpaddle speed. The number of tablets dissolved is 3 per batch.

FIGS. 23A-B show dissolution rates for 25 mg rofecoxib tablets. FIG. 23Ashows dissolution of 25 mg rofecoxib tablets in 1.5% SDS for batches 5and 6 at 75 rpm paddle speed. FIG. 23B shows dissolution of 25 mgrofecoxib tablets in 1.5% SDS for batches 5 and 6 at 50 rpm paddlespeed. The number of tablets dissolved is 3 per batch.

FIGS. 24A-B show dissolution rates for 25 mg rofecoxib tablets. FIG. 24Ashows dissolution of 25 mg rofecoxib tablets in 1% SDS for batches 5 and6 at 75 rpm paddle speed. FIG. 24B shows dissolution of 25 mg rofecoxibtablets in 1% SDS for batches 5 and 6 at 50 rpm paddle speed. The numberof tablets dissolved is 3 per batch.

Example 4 A Single-Dose, Open-Label, Phase 1, Adaptive PharmacokineticStudy of TRM-201 (Rofecoxib) 25 mg Administered to Healthy Subjects in aFasting State, with Comparison to Historical Pharmacokinetic Parametersof Previously Marketed Rofecoxib and a Food-Effect Substudy(“TRM-201-PK-101” or “101 PK Study”)

1. Study Protocol

1. Study Objectives

1.1 Primary Objective:

MAIN Study: To evaluate key PK parameters (AUG), of a single dose ofTRM-201 in healthy subjects in comparison to historical PK parameters(AUG), of previously marketed rofecoxib, both in a fasted state.

FOOD-EFFECT Substudy: To assess key pharmacokinetic parameters (AUG),Cmax) of a single dose of TRM-201 in a fasted and fed state.

1.2 Secondary Objectives:

1. To assess the safety and tolerability of a single dose of TRM-201 inhealthy subjects.

2. Investigational Plan

2.1 Study Design

This is a single-center, open-label, adaptive PK study of TRM-201consisting of a MAIN study with a PILOT portion conducted under a fastedcondition, and a two-period crossover, FOOD-EFFECT substudy under bothfasted and fed conditions. The PILOT portion of the study (21 subjects)will include a single dose of TRM-201 in a single group to assess the PKof TRM-201 in healthy volunteers under fasted conditions. Followingcompletion of the PILOT portion and the decision to move forward, anadditional 16 subjects will be enrolled in the MAIN study and anadditional 16 subjects will be enrolled in the FOOD-EFFECT substudy. TheMAIN study will include a single dose of TRM-201 to assess the PK ofTRM-201 in healthy volunteers under fasted conditions. The FOOD-EFFECTsubstudy is a single-dose, two-period crossover study. A single dose ofTRM-201 will be given on Day 1 of each dosing period to assess the PK ofTRM-201 in healthy volunteers under both fasted and fed conditions.Subjects will be randomized 1:1 into the two sequences fasted followedby fed, and fed followed by fasted.

The PK data from MAIN study (including the PILOT portion) will becombined with the PK data from the fasted portion of the FOOD-EFFECTsubstudy to form the basis of the comparison to historicalpharmacokinetic parameters of previously marketed rofecoxib. The PK datafrom the fed portion of the FOOD-EFFECT substudy will only be comparedwith the PK data from the fasted portion of the FOOD-EFFECT substudy.

PILOT Portion and MAIN Study

The subjects will be screened in the 28 days before receiving the singledose of TRM-201. Subjects will check in to the clinic on the day beforedosing, and their eligibility will be confirmed. Subjects will remain atthe clinic from Check-In through the completion of the end-of-study(EOS) visit on Day 6.

After Check-In, subjects will fast overnight for at least 10 hoursbefore study drug administration. While fasting, subjects will havenothing to eat and only water to drink. Water will be permitted asdesired, except for the period between 1 hour before and 1 hour afterstudy drug dosing (excepting as permitted for dosing). After the 2-hourPK blood sample, subjects will be allowed one 250-mL cup of clear applejuice. After the 4-hour PK blood sample, subjects will be served a lightlunch. Following the light lunch, subjects should receive standardizedmeals according to the clinic's standard procedures that are scheduledat consistent times and at least 15 minutes before or 15 minutes afterPK sampling time points. Blood will be withdrawn for PK analysis atpredefined time points as defined in Table 8. The last time point willbe 120 hours after dosing with study drug. After the 120-hour PK sample,the EOS procedures will be completed, and subjects will be dischargedfrom the clinic.

FOOD-EFFECT Substudy

The subjects will be screened in the 28 days before receiving the singledose of TRM-201. Subjects will check in to the clinic on the day beforedosing, and their eligibility will be confirmed. Subjects will remain atthe clinic from Check-In through the completion of the EOS visit on Day13 of Dosing Period 2.

After Check-In, subjects will fast overnight for at least 10 hoursbefore study drug administration. In the morning of the dosing day ofPeriod 1, subjects will be randomized in a 1:1 ratio within each genderto one of two dosing sequences:

-   -   Dosing sequence fasted/fed (8 subjects)    -   Dosing sequence fed/fasted (8 subjects)        Regardless of the dosing sequence assigned, all subjects will        undergo the same assessments, pre- and post-dose.

Fasted Group

While participating in the fasted portion of the substudy, subjects willfast overnight for at least 10 hours before study drug dosing. Whilefasting, subjects will have nothing to eat and only water to drink.Water will be permitted as desired, except for the period between 1 hourbefore and 1 hour after study drug dosing (excepting as permitted fordosing). After the 2-hour PK blood sample, subjects will be allowed one250-mL cup of clear apple juice. After the 4-hour PK blood sample,subjects will be served a light lunch. Following the light lunch,subjects should receive standardized meals according to the clinic'sstandard procedures that are scheduled at consistent times and at least15 minutes before or 15 minutes after PK sampling time points.

Blood will be withdrawn for PK analysis at predefined time points. Thelast time point will be 120 hours after dosing with study drug (Day 6).After the 120-hour PK sample, the EOP procedures will be completed.Subjects will fast overnight on Day 7 of Dosing Period 1 for at least 10hours and will commence with Dosing Period 2 in a fed condition on Day8.

Fed Group

While participating in the fed portion of the substudy, subjects willfast overnight for at least 10 hours before study drug dosing. Whilefasting, subjects will have nothing to eat and only water to drink priorto being fed a high fat breakfast. Subjects in the fed group will startthe high fat breakfast (defined per the FDA guidance as consisting oftwo eggs fried in butter, two strips of bacon, two slices of toast withbutter, four ounces of hash brown potatoes and eight ounces of wholemilk) 30 minutes prior to dosing with study drug. After the 4-hour PKblood sample, subjects will be served a light lunch. Following the lightlunch, subjects should receive standardized meals according to theclinic's standard procedures that are scheduled at consistent times andat least 15 minutes before or 15 minutes after PK sampling time points.

Blood will be withdrawn for PK analysis at predefined time points asdefined in Table 8. The last time point will be 120 hours after dosingwith study drug (Day 6). After the 120-hour PK sample, the EOPprocedures will be completed. Subjects will fast overnight on Day 7 ofPeriod 1 for at least 10 hours and will commence with Dosing Period 2 ina fasted condition on Day 8.

The time between dosing in Period 1 and 2 is 7 days. Subjects willcomplete Period 1 of the FOOD-EFFECT substudy on Day 6, but will remainin the clinic and subsequently be dosed on Day 8 to ensure a full 7-daywashout of study drug between Periods 1 and 2.

The assessments and requirements of Dosing Period 2 are the same asDosing Period 1. All assessments done on Dosing Period 2/Day 1 should bedone at approximately the same time of day as the assessments of DosingPeriod 1/Day 1.

A subject's participation in the study is complete after the EOS visitof Period 2.

Pharmacokinetic and safety endpoints will be evaluated in the study.

2.1.1 Rationale of Study Design

A scientific bridge will be established between TRM-201 and thepreviously marketed rofecoxib. Because there are presently noFDA-approved rofecoxib products commercially available globally withwhich to conduct a directly comparative bioavailability/bioequivalencestudy, the present study is designed to provide PK data for across-study comparison to a published study (Schwartz, J. I., et al.Clin. Drug Invent. 2003, 23 (8): 503-509; hereafter “the Schwartzstudy”).

The 25-mg dose of rofecoxib was selected for this study because it isthe anticipated maximum daily dose for the treatment of HA. The datafrom the Schwartz study were chosen for comparison because theyrepresent PK data generated with the labeled version of rofecoxib at 25mg. The eligibility criteria for this current PK study have beenselected to mirror the subject demographics and subgroups (gender, age,body mass index [BMI], race, and ethnicity) in the Schwartz study.

The FOOD-EFFECT substudy is a standard 2-period crossover studyevaluating TRM-201 in the fasted and fed states.

A validated bioanalytical method for rofecoxib will be developed andused for the PK analyses.

3. Subject Selection and Withdrawal Criteria

3.1 Selection of Study Population

A sufficient number of subjects will be screened to ensure that at least50 evaluable subjects complete the study.

In order to mirror the population of subjects in the Schwartz PK studyevery effort will be made to enroll subjects in the followingproportion: White or European American (80%), Black (20%). Of the Whitesubjects enrolled, every effort will be made to enroll approximately 60%of the subjects who identify themselves as being of Hispanic or Latinoethnicity.

Subjects will be enrolled only if they meet all the inclusion criteriaand none of the exclusion criteria and all of the continuing eligibilitycriteria. Deviations from the inclusion and exclusion criteria are notallowed because they can potentially jeopardize the scientific integrityof the study, regulatory acceptability, or subject safety. Therefore,adherence to the criteria as specified in the protocol is essential.

3.1.1 Inclusion Criteria

Inclusion Criteria:

-   -   1. The subject is male or female and is 18 to 60 years of age,        inclusive, at Screening. Similar numbers of male and female        subjects should be enrolled.    -   2. The subject has a BMI at Screening of 18 to 32 kg/m²,        inclusive, with a minimum weight of 47 kg for women and 66 kg        for men and a maximum weight of 80 kg for women and 90 kg for        men.    -   3. The subject is not a smoker (or user of e-cigarettes).    -   4. The investigator considers the subject to be in good general        health as determined by medical history, clinical laboratory        test results, vital sign measurements, 12-lead ECG results, and        physical examination findings at Screening and Check-in.    -   5. All female subjects must have a negative pregnancy test at        Screening. Female subjects of childbearing potential must also        have a negative pregnancy test at Check-in and must be using an        acceptable method of birth control during the study (i.e.,        diaphragm with spermicide, intrauterine device, condom with foam        or vaginal spermicide, oral contraceptives, or abstinence).        Women who are surgically sterile (i.e., hysterectomy, bilateral        tubal ligation or bilateral oophorectomy), or postmenopausal        (defined as amenorrhea for 12 consecutive months and documented        serum follicle-stimulating hormone level >40 IU/mL) are exempt        from the adequate contraception requirement.    -   6. The subject agrees to comply with all protocol requirements        as well as the particular requirements and specific Phase 1 unit        policies.    -   7. The subject provides written informed consent.

Exclusion Criteria:

-   -   1. The subject has a history of relevant drug allergy or food        allergy/sensitivity (e.g., allergy to rofecoxib or excipients of        TRM-201, allergy to other NSAIDs, or gluten intolerance that        could preclude consumption of a standard clinic diet).    -   2. A female subject is pregnant or lactating.    -   3. The subject has a history of intolerance or hypersensitivity        to aspirin or any other NSAID.    -   4. The subject has a positive test result for hepatitis B        surface antigen, hepatitis C virus antibody, or human        immunodeficiency virus types 1 or 2 antibodies at Screening.    -   5. The subject has used any prescription (excluding hormonal        birth control) or OTC medications including NSAIDs (i.e.,        ibuprofen, naproxen, and aspirin) as well as herbal or        nutritional supplements, within 14 days before the study drug        dosing. Subjects may have taken acetaminophen (up to 2 g per        day) in the 14 days prior to study drug dosing.    -   6. The subject has any clinically significant abnormalities        before dosing on Day 1 or has a history of disease, including:        uncontrolled or poorly controlled hypertension; asthma or        pulmonary disease; major cardiac ischemic symptoms, events, or        interventions such as angina pectoris, myocardial infarction,        acute coronary syndrome, decompensated congestive heart failure,        coronary stent or bypass; history of cerebrovascular ischemic        events (transient ischemic attack or stroke); major vascular        ischemic symptoms such as intermittent claudication or vascular        bypass or replacement surgery; significant cardiovascular, GI,        neurological, endocrine, or renal disease; hepatic impairment;        cholecystectomy; other condition known to interfere with the        absorption, distribution, metabolism, or excretion of drugs; or        clinically significant GI events.    -   7. The subject has a history or presence of any clinically        significant abnormality in vital signs, ECG, or laboratory        tests, or has any medical or psychiatric condition that, in the        opinion of the investigator, may interfere with the study        procedures or compromise subject safety (assessed at Screening        and Check-in).    -   8. The subject is a cigarette smoker or has used nicotine or        nicotine-containing products (e.g., snuff, nicotine patch,        nicotine chewing gum, e-cigarettes) within 6 months before study        drug dosing.    -   9. The subject has a history of alcohol abuse or drug addiction        within the last year or consumes more than 1 unit (1 unit is        equal to approximately ½ pint [200 mL] of beer, 1 small glass        [100 mL] of wine, or 1 measure [25 mL] of spirits) of alcohol a        day. Alcohol is not allowed within 7 days before study drug        dosing.    -   10. The subject has a positive test result for drugs of abuse,        alcohol, or cotinine (indicating active current smoking) at        Screening.    -   11. The subject is a habitual and heavy coffee drinker (more        than 4 cups a day, 28 cups a week).    -   12. The subject is involved in strenuous activity or contact        sports within at least 24 hours before study drug dosing.    -   13. The subject has donated blood or blood products within at        least 30 days before the dose of study drug in this study.    -   14. The subject has received study drug in another        investigational study within at least 30 days (or less than 5        half-lives of the investigational agent) prior to dosing in this        study.    -   15. The subject is not suitable for entry into the study, in the        opinion of the investigator.    -   16. The subject is an employee or family member of the        investigator or clinic staff.

Continuing Eligibility at Check-In

-   -   Applies to Day −1 of the PILOT portion, Day −1 of the MAIN study        and Day −1 of the first period of the FOOD-EFFECT substudy:    -   1. Females must have a negative serum pregnancy test.    -   2. All subjects must have a negative test results for drugs of        abuse and alcohol    -   3. Subjects must have had no significant changes in overall        health status since screening including the use of medications.    -   4. The subject is involved in strenuous activity or contact        sports within at least 24 hours before study drug dosing.

Subjects with test results which do not meet the aboveinclusion/exclusion criteria may have the relevant test repeated once ifit is thought to represent a laboratory error, a reversible, clinicallyinsignificant intermittent condition, or is not consistent with thesubject's historical values. If inclusion/exclusion criteria are not metafter the repeat test, the subject should be considered a screen failureand should not be enrolled in the study. Subjects may be retested once.

3.2 Withdrawal/Discontinuation of Subjects from the Study

The duration of the study is defined for each subject as the date signedwritten informed consent is provided through the EOS procedures.Participation in the study is scheduled for a maximum duration of 34days for each subject participating in the PILOT portion or MAIN study(27 days for Screening, 1 day for Check-In (Day −1), dosing on Day 1, PKblood sampling (Days 1-6), and the EOS procedures on Day 6) and 41 daysfor subjects who participate in the FOOD-EFFECT substudy. Period 1: 27days for Screening, 1 day for Check-In (Day −1), dosing on Day 1, PKblood sampling (Days 1-6), EOP on Day 6; Period 2: 1 additional day forstudy drug washout (Day 7), dosing on Day 8, PK blood sampling (Days9-13), and the EOS procedures on Day 13).

3.2.1 Reasons for Withdrawal/Discontinuation

Subjects may withdraw from the study at any time and for any reason.Every effort should be made to keep subjects in the study. The reasonsfor subjects not completing the study will be recorded. A subject mustbe withdrawn/discontinued from the study for any of the followingreasons:

-   -   1. The subject tests positive for pregnancy.    -   2. The subject withdraws consent to participate in the study.    -   3. The subject does not continue to meet the protocol inclusion        or exclusion criteria.    -   4. The subject experiences AEs or an AE that, in the        investigator's opinion, require(s) withdrawal from the study.    -   5. The subject is noncompliant with the protocol.    -   6. The investigator decides to withdraw the subject for any        medical reason.

A subject will also be discontinued if the study is terminated. Uponoccurrence of a serious or intolerable AE, the investigator will conferwith the sponsor. If a subject is discontinued because of an AE, theevent will be followed until it is resolved or considered clinicallystable.

3.2.2 Handling of Withdrawals/Discontinuations

Subjects are free to withdraw from the study at any time upon request.Subject participation in the study may also be stopped at any time.

Each subject in the PILOT portion and MAIN study is scheduled to receivea single dose of study drug. Subjects who participate in the FOOD-EFFECTsubstudy will receive a single dose of study drug twice, once in afasted condition and once in a fed condition. When a subject withdrawsfrom the PILOT portion, MAIN study, or FOOD-EFFECT substudy, thereason(s) for withdrawal shall be recorded by the investigator on therelevant page of the electronic case report form (eCRF). Wheneverpossible, any subject who receives a dose of study drug and thenwithdraws from the study prematurely will undergo all EOS assessmentsscheduled for Day 6 (Table 13).

It is vital to obtain follow-up data on any subject discontinued becauseof an AE or serious AE (SAE). In every case, efforts must be made toundertake protocol-specified, safety, follow-up procedures.

3.2.3 Subject Replacement

The intent is that subjects will not be replaced unless it is deemedthat a critical number of subjects are not evaluable.

4. Study Drug

This is an open-label PK study. Each subject is scheduled to receive asingle 25-mg dose of TRM-201 in the PILOT portion and the MAIN study,and a single 25-mg dose of TRM-201 twice in the FOOD-EFFECT substudy.TRM-201 manufactured and formulated as Batch 5 (B18090) and Batch 6(B18091), above, will be used in the study.

4.1 Administration of Study Drug

Study drug will be co-administered orally with approximately 250 mL ofroom temperature water, and up to an additional 250 mL of water will beallowed, if necessary, to aid in swallowing the study drug. Study staffwill ensure that at least 250 ml of water is consumed with the dose ofstudy drug and will perform a hand and mouth check after dosing toensure the tablet has been swallowed.

PILOT Portion and MAIN Study

After fasting for at least 10 hours overnight (Table 13), subjects willtake, a single dose (1 tablet) of TRM-201 on the morning of Day 1administered as described above, supervised by clinic staff. A hand andmouth check will be performed after dosing to ensure the tablet has beenswallowed. During the period between 1 hour before and 1 hour afterstudy drug dosing, subjects may drink only the water permitted for studydrug administration.

FOOD-EFFECT Substudy

Subjects will be randomized 1:1 into the two sequences: fasted followedby fed, and fed followed by fasted. During the fasted period, subjectswill fast and be administered a single dose of TRM-201 as describedabove. A hand and mouth check will be performed after dosing to ensurethe tablet has been swallowed. During the period between 1 hour beforeand 1 hour after study drug dosing, subjects may drink only the waterpermitted for study drug administration.

During the fed period, subjects will fast overnight for at least 10hours and will take a single dose (1 tablet) of TRM-201 as describedabove within at least 30 minutes of starting a high fat breakfast. Ahand and mouth check will be performed after dosing to ensure the tablethas been swallowed. During the period between 1 hour before and 1 hourafter study drug dosing, subjects may drink only the water permitted forstudy drug administration.

4.2 Identity of Study Drug

The study drug, TRM-201, is an immediate-release tablet that contains25-mg rofecoxib. The 7.25-mm diameter tablets are off-white, round, anduncoated with no markings. TRM-201 tablets are for oral administration.

TRM-201 tablets contain the active ingredient rofecoxib (25 mg) andinactive excipients. Each tablet contains the following inactiveexcipients: croscarmellose sodium, hydroxypropyl cellulose, lactose,magnesium stearate, microcrystalline cellulose, and yellow ferric oxide.All excipients comply with standards described in United StatesPharmacopeia-National Formulary, European Pharmacopeia, and JapanesePharmacopeia.

4.3 Management of Clinical Supplies

4.3.1 Study Drug Packaging and Storage

TRM-201 oral tablets will be provided as bulk supply in high-densitypolyethylene bottles. All packaging and labeling will be performedaccording to Good Manufacturing Practice and Good Clinical Practice(GCP) rules. The lot number and date of manufacture for the clinical lotused in the study will be provided to the clinical site and will bereported in the Clinical Study Report. All study drug will be labeledwith:

Protocol number

Sponsor's name and address

Investigational New Drug statement

Instructions for use and storage

All study drug must be stored at 20 to 25° C. (excursions permitted inthe range of 15 to 30° C.), in accordance with the labeled instructions,in a secure cabinet or room with access restricted to necessary clinicpersonnel. The site will keep a temperature log to establish a record ofcompliance with storage conditions.

The clinical unit pharmacy will prepare the dosing for each subjectaccording to the schedule of events (Table 13).

4.3.2 Study Drug Accountability

The investigator will maintain accurate records of receipt of all studydrug, including dates of receipt. In addition, accurate records will bekept regarding when and how much study drug is dispensed and used byeach subject in the study. Reasons for departure from the expecteddispensing regimen must also be recorded on standard clinic drugaccountability and packaging forms. At the completion of the study, tosatisfy regulatory requirements regarding drug accountability, all studydrug will be reconciled and retained or destroyed according toapplicable regulations.

4.4 Method of Assigning Subjects to Treatment

In the PILOT portion, subjects who meet all inclusion criteria and noneof the exclusion criteria and all of the continuing eligibility criteriawill receive TRM-201 according to the schedule of events (Table 13).Similar numbers of male and female subjects should be enrolled.Additional subjects may be screened to attain the overall demographicparameters of the subjects enrolled in the Schwartz PK study.

Once a decision to continue is made after the PILOT portion iscompleted, subjects will be screened to enter the MAIN study or theFOOD-EFFECT substudy. In the MAIN study and FOOD-EFFECT substudy,subjects who meet all of the inclusion criteria and none of theexclusion criteria and all of the continuing eligibility criteria willreceive TRM-201 according to the schedule of events (Table 13).

Similar numbers of male and female subjects should be enrolled.Additional subjects may be screened to attain the overall demographicparameters of the subjects enrolled in the Schwartz PK study.

Subjects will be randomized in a 2:1:1 ratio to one of three groups:

-   -   Main study—fasted (16 subjects)    -   FOOD-EFFECT substudy—fasted/fed sequence (8 subjects)    -   FOOD-EFFECT substudy—fed/fasted sequence (8 subjects)

4.5 Blinding

This is an open-label study: there is no blinding of study drug.

4.6 Treatment Compliance

All doses of study drug will be administered in the clinic under directobservation of clinic staff and will be recorded in the eCRF. Clinicstaff will confirm that the subject has swallowed the dose of studydrug.

The date and time of study drug dosing will be recorded on theappropriate page of the eCRF.

4.7 Prior and Concomitant Therapy

The investigator or designee must record the use of prior medications(all medication taken within at least 28 days before Screening) andconcomitant therapy (including both drug and nondrug therapies and allprescribed, OTC, and alternative medicines) in the eCRF. This includesdrugs that are used as-needed. Any changes in concomitant medicationswill also be recorded in the subject's eCRF. The minimum requirement isthat the drug name and dates of dosing are to be recorded.

Use of prescription medications (excluding hormonal birth control) andOTC medications (except acetaminophen), including NSAIDs (i.e.,ibuprofen, naproxen, and aspirin) as well as herbal or nutritionalsupplements (exclusion criterion 5), is prohibited from 14 days beforestudy drug dosing through the EOS. Use of acetaminophen is prohibitedfrom Check-In through the EOS. Violation of these prohibitions willresult in the subject's discontinuation from the study.

5. Study Procedures, Assessments, and Endpoints

Before performing any study procedures, all potential subjects will signan informed consent form (ICF). Subjects will have the opportunity tohave any questions answered before signing the ICF. The investigatormust address all questions raised by the subject. The investigator ordesignee will also sign the ICF.

The schedule of events for the study is presented in Table 13. The ECGrecordings must precede blood sampling for PK assessments at thespecified time points on Day 1 and at the EOS visit, and PK bloodsampling must occur within the sampling windows. Timings of PK bloodsampling and ECG assessments will be calculated from time ‘0’, the timeof study drug dosing on Day 1 and complete on Day 6 at the 120 hour PKsample draw and from time ‘0’, the time of study drug dosing on Day 8and complete on Day 13 for subjects who participate in the FOOD-EFFECTsubstudy.

TABLE 13 Schedule of Events Period-2 Pharmacokinetic Subjects PhaseScreening Check-in Sampling EOP/EOSg Only Day −28 to −2 −1 1 2 3 4 5 6 7Period-2 Days 8 9 10 11 12 13 Informed consent X Demographics X Medicalhistory X X Viral serology X Serum follicle-stimulating X hormone(females only) Admission to clinic X Serum pregnancy test X X X (femalesonly) Urine drug screen (including X X alcohol and cotinine) Clinicallaboratory testing X X X (blood/urine) Height, weight, and X weightweight body mass index ONLY ONLY Physical examination^(a) X X X (EOSONLY) Vital sign measurements^(b) X X X X X X X 12-Lead ECGassessment^(c) X X X X (EOS ONLY) Eligibility assessment (initial X Xand continuing) PILOT, MAIN STUDY and X X X X X X X X fasted-period mealscheduled^(i) Study drug administration^(e) FOOD-EFFECT fed-period X X XX X X X X meal scheduler^(f) Pharmacokinetic sample X X X X X collection(see Table 8) Adverse event assessment X X X X X X Prior or concomitantmedication X X X X X X X assessment Discharge from clinic X (EOS ONLY)Abbreviations: ECG, electrocardiogram; EOS, end of study; EOP, end ofperiod. Note: The order of procedures on each day should follow theorder of presentation in Table 13 (top to bottom). When proceduresoverlap or occur at the same time point, all blood sampling shouldfollow vital signs or ECGs, and PK sampling should be timed to occurlast and as close to the scheduled time window as possible. Timings ofPK blood sampling and electrocardiogram assessments will be calculatedfrom time “0”, the time of study drug dosing. Period-2 subjects willremain in the clinic and be dosed on Day 8, 2 days after EOP. ^(a)A fullphysical examination will be performed at Screening (at minimum,assessment of skin, head, ears, eyes, nose, throat, neck, thyroid,lungs, heart, cardiovascular, abdomen, lymph nodes, and musculoskeletalsystem/extremities). A brief physical examination will be performed atCheck-In and EOS (at minimum, assessment of skin, lungs, cardiovascularsystem, and abdomen). Interim physical examinations may be performed atthe discretion of the investigator, if necessary, to evaluate adverseevents or clinical laboratory abnormalities. ^(b)Vital signs willinclude systolic and diastolic blood pressure, pulse rate, respiratoryrate, and oral body temperature, after the subject has been seated forat least 5 minutes. On Day 1 (and Day 8 of FOOD-EFFECT study), vitalsigns will be measured within 120 minutes before study drug dosing andat the 2-hour, 3-hour and 7.5-hour time points. At these time points(2h, 3h and 7.5 h) only systolic and diastolic blood pressure, pulserate and respiratory rate will be assessed. On Days 2 through 6, vitalsigns will be assessed within 15 minutes before the first PK bloodsample of the day. See Note. ^(c)After the subject has been in thesupine position for at least 5 minutes, single 12-lead ECG recordingswill be taken at Screening, Check-in, the 2-hour and 3-hour time point,and EOS. ^(d)For all portions of the study the fasting period will beginat the day of Check-In, for at least 10 hours overnight before studydrug administration and again on Day 7 for the FOOD-EFFECT study.^(e)Study drug will be administered after vital sign measurements havebeen completed. Study drug will be administered with −250 mL of roomtemperature water. Up to an additional −250 mL of water will be allowed,if necessary, to aid in swallowing the study drug. Subjects willmaintain an upright position (seated or standing) for at least 4 hoursafter dosing. Dosing for Period-2 subjects must occur at least 7 daysafter Period-1 dosing. fFOOD-EFFECT substudy - fed portion: Subjectswill fast at least 10 hours overnight. In the morning prior to studydrug administration they will be given a high-fat breakfast to begin atleast 30 minutes prior to dosing. After the 4-hour PK blod sampling.Subjects shoud then receive standardized meals according to the clinic'sstandard procedures and scheduled at consistent times. Meal may beginimmediately after a PK timepoint and should end at least 15 minutesbefore a PK sampling time point. ^(g)For subjects in the FOOD-EFFECTsubstudy - this visit is considered the end of the period (EOP) forDosing Period 1 and EOS after Dosing Period 2.

5.1 Pharmacokinetic Procedures, Assessments, and Endpoints

The time points and windows for PK blood sampling for the PILOT portion,Main study and FOOD-EFFECT substudy are presented in Table 14 below. Foreach sample, approximately 3 mL of blood will be drawn. The samples maybe obtained by a straight stick or via an in-dwelling intravenous (IV)catheter in a forearm vein. Additional details for the collection,processing, storage, and shipping of PK samples will be provided in thestudy manual.

TABLE 14 Times and Windows for Pharmacokinetic Blood Sampling for PILOTportion, Main Study and FOOD-EFFECT substudy Unit of Time Minutes HoursTimepoint 0^(a) 15 30 45 1 1.5 2 3 4 5 6 7.5 9 12 15 18 21 24 27 30 3336 39 42 48 52 60 72 96 120 Window ±5 min ±10 min ±15 min ±30 min ±60min (min) Abbreviation: min; minutes. ^(a)The blood sample for time 0should be taken within 1 hour before dosing with study drug, and priorto breakfast in the fed-state period. Note - Samples will be collectedafter each rofecoxib dose in the food-effect substudy

Pharmacokinetic samples will be analyzed using a validated assay forrofecoxib in human plasma. Assay results and validation details will beprovided in a separate bioanalytical report.

The following PK parameters for rofecoxib will be calculated as primaryendpoints using standard noncompartmental methods for both the PILOTportion and MAIN study, and the FOOD-EFFECT substudy: AUC_(0-∞) andC_(max). Secondary endpoints include T_(max), and t_(1/2). Additional PKparameters (e.g., CL/F, and V_(d)/F) will also be calculated usingstandard noncompartmental methods.

5.2 Safety Assessments

The timing and frequency of all safety assessments is listed in theschedule of events (Table 13).

Safety and tolerability will include monitoring and recording of AEs,clinical laboratory assessments (hematology, serum chemistry, andurinalysis), vital sign measurements, 12-lead ECG assessments, andphysical examination findings.

For all safety assessments, the investigator will determine whetherresults are clinically significant, which is defined as any variation ina result that has medical relevance and may result in an alteration inmedical care (e.g., active observation, diagnostic measures, ortherapeutic measures). If clinical significance is noted, the result andreason for significance will be documented on the AE page of thesubject's eCRF and the investigator will monitor the subject until theresult has reached the reference range or the result at Screening, oruntil the investigator determines that follow-up is no longer medicallynecessary.

Any abnormal laboratory test results (hematology, clinical chemistry, orurinalysis) or other safety assessments (e.g., ECGs, vital signmeasurements), including those that worsen from baseline, felt to beclinically significant in the medical and scientific judgment of theinvestigator are to be recorded as AEs or SAEs.

5.2.1 Adverse Events

5.2.1.1 Definitions of Adverse Events

The investigator is responsible for reporting all AEs that are observedor reported during the study, regardless of their relationship to studydrug or their clinical significance. If there is any doubt as to whethera clinical observation is an AE, the event should be reported.

An AE is defined as any untoward medical occurrence in a subjectenrolled into this study regardless of its causal relationship to studydrug. Subjects will be instructed to contact the investigator at anytime after enrollment if any symptoms develop.

A treatment-emergent AE (TEAE) is defined as any event not presentbefore exposure to study drug or any event already present that worsensin either intensity or frequency after exposure to study drug.

5.2.1 Serious Adverse Events

An SAE is defined as any event that

-   -   results in death    -   is immediately life threatening    -   requires inpatient hospitalization or prolongation of existing        hospitalization    -   results in persistent or significant disability/incapacity    -   is a congenital anomaly/birth defect

Important medical events that may not result in death, be lifethreatening, or require hospitalization may be considered SAEs when,based upon appropriate medical judgment, they may jeopardize the subjector may require medical or surgical intervention to prevent one of theoutcomes listed in this definition. Examples of such medical eventsinclude allergic bronchospasm requiring intensive treatment in anemergency room or at home, blood dyscrasias or convulsions that do notresult in inpatient hospitalization, or the development of drugdependency or drug abuse.

5.2.1.3 Eliciting and Documenting Adverse Events

Adverse events will be assessed from the time of study drug dosing untilall EOS procedures are complete.

Subjects will be asked a standard nonleading question to elicit anymedically related changes in their well-being.

In addition to subject observations, AEs identified from any study data(e.g., laboratory values, physical examination findings, ECG changes) oridentified from review of other documents that are relevant to subjectsafety will be documented on the AE page in the eCRF.

5.2.1.4 Reporting Adverse Events

All AEs reported or observed during the study will be recorded on the AEpage in the eCRF. Information to be collected includes the following:

-   -   event term    -   time of onset    -   investigator-specified assessment of severity and relationship        to study drug    -   time of resolution of the event    -   seriousness    -   any required treatment or evaluations    -   outcome

All AEs will be followed to adequate resolution. The Medical Dictionaryfor Regulatory Activities (MedDRA; Version 21.1) will be used to codeall AEs.

5.2.1.5 Reporting Serious Adverse Events

Any AE that is considered serious by the investigator or which meets SAEcriteria must be reported to the medical monitor (i.e., within at least24 hours) after the clinic staff first learn about the event. Theinvestigator will assess whether there is a reasonable possibility thatthe study drug caused the SAE.

5.2.1.6 Suspected Unexpected Serious Adverse Reactions

The sponsor will promptly evaluate all suspected unexpected seriousadverse reactions (SUSARs) against cumulative product experience toidentify and expeditiously communicate possible new safety findings tothe investigator, IRB, and applicable health authorities based onapplicable legislation.

To determine reporting requirements for single AE cases, the sponsorwill assess the expectedness of these events using the TRM-201investigator's brochure. The sponsor will compare the severity of eachSUSAR, and the cumulative event frequency reported for the study withthe severity and frequency reported in the TRM-201 investigator'sbrochure.

Reporting requirements will also be based on the investigator'sassessment of causality and seriousness, with allowance for upgrading bythe sponsor as needed.

5.2.1.7 Assessment of Severity

The severity, or intensity, of an AE refers to the extent to which an AEaffects the subject's daily activities. The intensity of the AE will berated as mild, moderate, or severe using the following criteria:

-   -   Mild: These events require minimal or no treatment and do not        interfere with the subject's daily activities.    -   Moderate: These events result in a low level of inconvenience or        require minor therapeutic measures. Moderate events may cause        some interference with normal functioning.    -   Severe: These events interrupt a subject's usual daily activity        and may require systemic drug therapy or other treatment. Severe        events are usually incapacitating.

Changes in the severity of an AE should be documented to allow anassessment of the duration of the event at each level of intensity to beperformed. Adverse events characterized as intermittent do not requiredocumentation of onset and duration of each episode.

5.2.1.8 Assessment of Causality

The investigator's assessment of an AE's relationship to study drug ispart of the documentation process, but it is not a factor in determiningwhat is or is not reported in the study.

The investigator will assess causality (i.e., whether there is areasonable possibility that the study drug caused the event) for all AEsand SAEs. The relationship will be classified as follows:

-   -   Not related: There is not a reasonable possibility of        relationship to study drug. The AE does not follow a reasonable        temporal sequence from study drug administration, or can be        reasonably explained by the subject's clinical state or other        factors (e.g., disease under study, concurrent diseases, and        concomitant medications).    -   Related: There is a reasonable possibility of relationship to        study drug. The AE follows a reasonable temporal sequence from        study drug administration and cannot be reasonably explained by        the subject's clinical state or other factors (e.g., disease        under study, concurrent diseases, or concomitant medications),        represents a known reaction to the study drug or other drugs in        its class, is consistent with the known pharmacological        properties of the study drug (and/or recurs with re-challenge,        if applicable).

5.2.1.9 Follow-Up of Subjects Reporting Adverse Events

All AEs must be reported in detail on the appropriate page in the eCRFand followed to satisfactory resolution, until the investigator deemsthe event to be chronic or not clinically significant, or until thesubject is considered stable.

5.2.2 Clinical Laboratory Assessments

The following clinical laboratory assessments will be performed:

Hematology: hematocrit, hemoglobin, mean corpuscular hemoglobin, meancorpuscular hemoglobin concentration, mean corpuscular volume, plateletcount, red blood cell count, and total and differential leukocyte count

Serum Chemistry: Alanine aminotransferase, albumin, alkalinephosphatase, aspartate aminotransferase, bilirubin (total), blood ureanitrogen, calcium, carbon dioxide, chloride, total cholesterol, creatinephosphokinase, creatinine, gamma-glutamyltransferase, globulin, glucose,lactate dehydrogenase, phosphorus, potassium, sodium, total protein,triglycerides, and uric acid

Urinalysis: Appearance, bilirubin, color, glucose, ketones, leukocyteesterase, reflex microscopy (performed if dipstick is positive forprotein or the blood value is 1+ or greater; and includes bacteria,casts, crystals, epithelial cells, red blood cells, and white bloodcells), nitrites, occult blood, pH, protein, specific gravity,turbidity, and urobilinogen

Serology: Hepatitis B surface antigen, hepatitis C virus antibody, andhuman immunodeficiency virus antibody types 1 and 2 (Screening only)

Other analyses: All subjects: Urine drug screen (alcohol, amphetamines,barbiturates, benzodiazepines, cannabinoids, cocaine, cotinine,methylenedioxymethamphetamine, opiates, phencyclidine, propoxyphene, andtetrahydrocannabinol) Female subjects: serum Follicle-stimulatinghormone, serum and urine β-human chorionic gonadotropin.

The clinical laboratory that performs the tests will provide thereference ranges for all clinical laboratory parameters. Clinicallaboratory tests may be repeated at the discretion of the investigator,if necessary, for assessment of inclusion and exclusion criteria orevaluation of clinical laboratory abnormalities.

5.2.3 Vital Sign Measurements

Vital signs will include systolic and diastolic blood pressure, pulserate, respiratory rate, and oral body temperature, after the subject hasbeen seated for at least 5 minutes. Vital sign measurements will beconducted within the 120 minutes before dosing of study drug (applicableon Day 1 only) and 15 minutes before any blood sampling. A single repeatmeasurement is permitted at Screening to determine eligibility andCheck-In to confirm continued eligibility. On Day 1 and Day 8 (DosingPeriod 2 of FOOD-EFFECT study) systolic and diastolic blood pressure,pulse rate and respiratory rate will be assessed at the 2-hour, 3-hourand 7.5 hour time points.

5.2.4 Electrocardiogram Assessments

After the subject has been in the supine position for at least 5minutes, single 12-lead ECG recordings will be made at Screening,Check-in, the 2-hour and 3-hour time points, and EOS. A single repeatmeasurement is permitted at Screening to determine eligibility and atCheck-In to confirm continued eligibility. Measurements of the followingintervals will be reported: RR interval, PR interval, QRS width, QTinterval, and QTcF and may be interpreted for abnormality by the ECGmachine. Any abnormalities including rhythm; presence of arrhythmia orconduction defects; morphology; any evidence of myocardial infarction;or ST-segment, T-Wave, and U-Wave abnormalities should be assessed forclinical significance and noted.

5.3 Pregnancy

Pregnancy is not regarded as an AE unless there is a suspicion that aninvestigational product may have interfered with the effectiveness of acontraceptive medication. Any pregnancy that is detected after studydrug administration and during study participation must be reportedusing the same procedures as an SAE, but using a clinical studypregnancy form. The pregnancy must be followed up (with the subject'sconsent) to determine outcome (including spontaneous miscarriage,elective termination, normal birth, or congenital abnormality) andstatus of mother and child, even if the subject was discontinued fromthe study. Pregnancy complications and elective terminations for medicalreasons should not be reported as an AE or SAE. Spontaneous miscarriagesmust be reported as an SAE.

Any SAE occurring in association with a pregnancy, brought to theinvestigator's attention after the subject has completed the study, andconsidered by the investigator as possibly related to the studytreatment, must be promptly reported to the Sponsor.

5.3.1 Physical Examination Findings

A full physical examination will be performed at Screening (at minimum,assessment of skin, head, ears, eyes, nose, throat, neck, thyroid,lungs, heart, cardiovascular, abdomen, lymph nodes, and musculoskeletalsystem/extremities). A brief physical examination will be performed atCheck-In and at the EOS. At a minimum, assessment of skin, lungs,cardiovascular system, and abdomen will be performed. Interim physicalexaminations may be performed at the discretion of the investigator, ifnecessary, to evaluate AEs or clinical laboratory abnormalities. 5.4Sample Collections

The total amount of blood collected from each subject over the durationof the study is expected to be approximately 130 mL (PK samples: 90 mL,clinical laboratory samples: 40 mL) for subjects participating in thePILOT portion and MAIN study and approximately 220 mL (PK samples: 180mL, clinical laboratory samples: 40 mL) for subjects participating inthe FOOD-EFFECT study. Additional assessments may be required, but themaximum amount of blood drawn for any subject will not exceed 250 mL.

6. Statistical and Analytical Plan

The interim analysis of the PILOT portion is only for futility; hence,there is no impact of that interim analysis on the type-1 errorpotential for the final analyses (all fasted data from PILOT portion,MAIN study, and the FOOD-EFFECT substudy combined).

6.1 Sample Size Calculations

6.2 Comparability of TRM-201 with Previously Marketed Rofecoxib

Consistent with the Schwartz study, the total sample size of 50evaluable subjects is considered sufficient for the objectives of thestudy. Back-calculation of summary statistics from the Schwartz datayielded natural-log-scale SDs of 0.33 and 0.31 for AUC_(0-∞) and Cmax,respectively. Power is computed as the probability that the upper limitof a 90% CI for the geometric mean ratio (GMR=observed geometric meanfrom this trial divided by the historical control value) for theseparameters falls below 1.25. Assuming a natural-log-scale SD equal to0.33, N=50 has approx. 80% power if the TRUE underlying geometric meanratio (GMR)=1.11, and approximately 90% power if the TRUE underlyingGMR=1.08. The maximum OBSERVED GMR that would reject the null hypothesisis 1.15. The power for C_(max) is slightly greater since associated SDis smaller than that for AUC_(0-∞); however, for perspective on actualvalues for the new formulation, Table 15 shows AUC_(0-∞) and C_(max)geometric mean values associated with the ratios computed from SD=0.33.

TABLE 15 Power Estimates for Comparability between TRM-201 andPreviously Marketed Rofecoxib Geometric Mean Ratios Maximum OBS.Fold-Incr for 1.15^(a) Comparability TRUE Fold-Incr. for ~80% power1.11^(a) TRUE Fold-Incr. for ~90% power 1.08^(a) Historical mean 1.25Times PK Geometric value from the the historical Parameter ParameterMeans Schwartz study mean value C_(max) Max. OBS. Geo.Mean for 250 217C_(max) 25 mg 271 Comparability TRUE Geo.Mean for ~80% power 241 217 271TRUE Geo.Mean for ~90% power 234 217 271 AUC_(0-∞) Max. OBS.Geo. Meanfor 4369 3799 AUC_(0-∞) 4749 Comparability 25 mg TRUE Geo.Mean for ~80%power 4217 3799 4749 TRUE Geo.Mean for ~90% power 4103 3799 4749 C_(max)Max. OBS.Geo. Mean for 281 244 C_(max) 12.5 mg 305 Comparabilitydose-adjusted TRUE Geo.Mean for ~80% power 271 244 to 25 mg 305 TRUEGeo.Mean for ~90% power 264 244 305 Abbreviations: Geo.Mean, geometricmean; Incr, increase; Max., maximum; OBS., observed. ^(a)Fold-increaseexpressed relative to the historical mean value

6.1.2 Comparison of TRM-201 Under Fed and Fasted Conditions

There are not pre-specified bounds for the fed/fasted GMR's for AUC andCmax derived from the FOOD-EFFECT substudy. However, those GMR's andassociated 90% CI's will be derived from the 2-period crossover model toestimate the food effect. Koytchev, et al. reported data from whichintra-subject SD's for AUC and Cmax were back-calculated as 0.11 and0.14 on the natural-log-scale, respectively (Koytchev, R. et al.,Arzneimittelforschung, 2004, 54(9), 624-628). Conservatively, using thevalue 0.15 for natural log-scale within-subject SD, Table 16 belowindicates 90% CI's for GMR, back-transformed from the natural-logcalculation scale via a standard crossover design ANOVA.

TABLE 16 Power estimates for FOOD-EFFECT Substudy OBSERVED N = 12 N = 15GMR 90% LCL 90% UCL 90% LCL 90% UCL 0.5 0.45 0.56 0.45 0.55 0.67 0.600.75 0.61 0.74 0.8 0.72 0.89 0.73 0.88 1 0.89 1.12 0.91 1.10 1.25 1.121.40 1.13 1.38 1.5 1.34 1.68 1.36 1.65 2 1.79 2.23 1.82 2.20 NOTE:calculations via standard 2-period crossover design ANOVA assumingnatural-log-scale SD = 0.15

6.2 Analysis Sets

The following analysis sets will be used in the statistical analyses:

The PK analysis set will include subjects who receive a single dose ofTRM-201 and have sufficient concentration data to support accurateestimation of at least one PK parameter. Subjects who experiencevomiting within at least 2 times the median T_(max) (approximately 6hours) after study drug dosing will be excluded from the PK analysis.

The PK data from Main study (including the PILOT portion) will becombined with the PK data from the fasted portion of the FOOD-EFFECTsubstudy to form the basis of the comparison to historicalpharmacokinetic parameters of previously marketed rofecoxib. The PK datafrom the fed portion of the FOOD-EFFECT substudy will only be comparedwith the PK data from the fasted portion of the FOOD-EFFECT substudy.

The safety analysis set will include all subjects who receive at least 1dose of study drug.

6.3 Description of Subgroups to be Analyzed

The relationship of AUC_(0-∞) and C_(max) to age and to BMI will each beassessed via scatter plots and correlation coefficients. If appropriate,additional modeling of those relationships may be carried out. Summarystatistics for AUC_(0-∞) and C_(max) will be provide by gender, agecategories (divided into tertiles), race categories, and ethnicitycategories.

6.4 Statistical Analysis Methodology

Details of all statistical analyses will be described in a separatestatistical analysis plan. All data collected will be presented in datalistings. Data from subjects excluded from an analysis population willbe presented in the data listings but will not be included in thecalculation of summary statistics or statistical analysis.

For categorical variables, frequencies and percentages will bepresented. Continuous variables will be summarized using descriptivestatistics (number of subjects, mean, median, SD, minimum, maximum,geometric mean, natural-log-scale SD).

Baseline demographic and background variables will be summarized overallfor all subjects. The number of subjects who enroll in the study and thenumber and percentage of subjects who complete the study will bepresented. Frequency and percentage of subjects who withdraw ordiscontinue from the study, and the reason for withdrawal ordiscontinuation, will also be summarized. Statistical analysis will beperformed using SAS software Version 9.4 or later. Continuous variableswill be summarized using the mean, the standard deviation, median,minimum value, and maximum value. Categorical variables will besummarized using frequency counts and percentages. Data will be listedin data listings.

6.4.1 Analysis of Pharmacokinetic Endpoints

Individual plasma concentrations for rofecoxib and PK sampling timedeviation data will be presented in a data listing. Plasma concentrationdata will be summarized by time point using the following descriptivestatistics: number of subjects, arithmetic mean, SD, coefficient ofvariation (CV), geometric mean, natural-log-scale SD, geometric CV,median, minimum, and maximum. Individual plasma concentration versusactual time profiles will be presented on both linear andsemilogarithmic scales. Additionally, arithmetic mean concentrationversus scheduled time profiles will be presented on linear scales andgeometric means on semilogarithmic scales.

The PK parameters of rofecoxib will be analyzed based on the actualsampling times. All parameters will be calculated using the Phoenix®WinNonlin® version 6.4 or higher (Certara USA Inc., Princeton, N.J.) orSAS® version 9.3 or higher (SAS Institute Inc., Cary, N.C.). Theindividual PK parameters will be presented in data listings.

6.4.1.1 PILOT Portion, MAIN Study and FOOD-EFFECT Substudy

Summary statistics for the primary PK endpoints, AUC_(0-∞) and Cmax,will include n, arithmetic mean, CV, SD, geometric mean,natural-log-scale SD, median, minimum, and maximum, along with theassociated 90% CI computed on the natural-log-scale and back-transformedto the original measurement scale. The GMR to historical control valuesand associated 90% CIs will be computed on log scale andback-transformed to the ratio scale; the reference values are from theSchwartz study: 3799 ng·hr/mL and 217 ng/mL for AUC_(0-∞) and C_(max),respectively.

Without being bound by theory, the primary hypotheses for both AUC_(0-∞)and C_(max) are:

-   -   Null Hypothesis: the TRUE underlying GMR (new formulation versus        historical control) is at least 1.25    -   Alternative Hypothesis: the TRUE underlying GMR (new formulation        versus historical control) is less than 1.25

These null hypotheses will each be tested via comparing to 1.25 theupper limit of a 90% CI for the geometric mean computed on thenatural-log-scale and back-transformed to the original scale. If theupper 90% CI lies below 1.25 times the historical control geometric meanvalue, the null hypothesis will be rejected, and the alternativehypothesis will be concluded. The AUC_(0-∞) and C_(max) null hypothesesneed to be rejected to support a conclusion that the new formulation issufficiently similar to the formulation that yielded the historicalcontrol data.

Sensitivity analyses will be carried out separately for AUC_(0-∞) andC_(max) using age- and race-adjusted geometric means that match the meanage and race distribution of the historical control data. Secondaryanalyses similar to the primary will be carried out in comparison to alower limit of 0.8 times the respective historical control values.

The T_(max) will be summarized by n, arithmetic mean, CV, SD, median,minimum, maximum, and 90% CI for the median via normal approximation.Apparent t_(1/2) will be summarized by n, arithmetic mean, CV, SD,harmonic mean, jack-knife SD, median, minimum, and maximum. The 90% CIfor harmonic mean will be computed on the inverse scale andback-transformed to the actual scale. The 90% CIs for median T_(max) andharmonic mean t_(1/2) will be compared to their respective historicalcontrol values.

In addition to the proposed statistical approach to calculate themaximum observed geometric mean ratio for the primary PK parametersusing the traditional bioequivalence reference range of 1.25, analternative approach considered incorporating the variability in the PKparameters observed in the Schwartz study. The results for the maximumobserved geometric mean ratio for AUC_(0-∞) and C_(max) that would yield90% CI<1.33 were similar to those of the proposed approach.

Summary statistics for the secondary PK endpoints, including apparentplasma clearance (CL/F) and apparent volume of distribution (V_(d)/F)will include n, arithmetic mean, SD, CV, geometric mean,natural-log-scale SD, median, minimum, maximum, along with theassociated 90% CI computed on the natural-log-scale and back-transformedto the original measurement scale, as appropriate.

6.4.1.2 FOOD-EFFECT Sub-Study (all PK Parameters from Subjects WhoReceived 2 Single Doses, One Fasted, and One Fed)

The PK parameters computed from the FOOD-EFFECT substudy will beanalyzed via the standard 2-period crossover design ANOVA includingfactors for treatment, period, and subject via the same transformationsas for the MAIN study. The same summary statistics for the FOOD-EFFECTstudy will be derived from that analysis model via similar methods asfor the MAIN study, however, there are no pre-specified criteria for theAUC and Cmax GMR 90% CI's.

6.4.2 Analysis of Safety Endpoints

All safety data will be summarized for the PILOT portion, MAIN study,and FOOD-EFFECT substudy combined. Subjects who received 2 single doseswill be counted once with all of their safety data combined. Theincidence of adverse events will be presented by the MedDRA system organclass and preferred term, relationship to the test article, andseverity. Descriptive statistics of clinical laboratory results andvital signs will be presented, as well as summaries of changes frombaseline (from the Check-in visit(s)) and of clinically notable values.

All AE data will be presented in a data listing by study part and withinthe FOOD-EFFECT substudy by treatment sequence. TEAEs will be summarizedoverall, as well as by severity and relationship to study drug. SeriousAEs and AEs leading to discontinuation of study drug will also bepresented in the data listings and summarized.

Actual values and changes from Baseline for clinical laboratory testresults, vital sign measurements, and 12-lead ECG results will besummarized at each time point using descriptive statistics (number ofsubjects, mean, SD, median, minimum, and maximum). Shift tables will begenerated for clinical laboratory test results. Physical examinationfindings will be presented in a data listing.

6.4.3 Other Analyses

Summary statistics will be provided for demographics, medical history,physical examination and social history.

6.4.4 Handling of Missing Data

Plasma concentrations that are below the limit of quantification (BLQ)will be treated as zero for descriptive statistics. Mean BLQconcentrations will be presented as BLQ, and the SD and CV will bereported as not applicable. Missing concentrations will be excluded fromthe calculations.

For the PK analysis, BLQ values will be treated as zero with theexception that a BLQ value between 2 quantifiable concentrations will beset as missing. Missing concentrations will be treated as missing fromthe PK parameter calculations. If consecutive BLQ concentrations arefollowed by quantifiable concentrations in the terminal phase, thoseconcentrations after BLQ concentrations will be treated as missing.

6.4.5 Interim Analyses

Samples will be assayed, and PK calculations will be performed on thesamples obtained from the subjects enrolled in the PILOT study. Ifsubstantial differences in the exposure of TRM-201 are observed in thePILOT study compared to the expected historical data for rofecoxib thestudy may not continue with the current formulation of study drug.

Note that the interim analysis of the PILOT portion is only forfutility; hence, there is no impact of that interim analysis on the type1 error potential for the final analyses (all fasted data from the PILOTportion, MAIN study, and the FOOD-EFFECT substudy combined).

B. Results from PK 101 Pharmacokinetic Study

The Cmax and AUC_(0-∞) values in individual subjects for a 25 mg dosageof rofecoxib (TRM-201) are presented in Table 17 below.

TABLE 17 AUC and Cmax values by subject (fasted) AUC Infinity Total CLObs Max Conc Half-Life Time of Subject Obs (h * ng/mL) by F (L/h)(ng/mL) Lambda z (h) CMAX (h) Vz Obs by F (L) 100-001 4789.36 5.22 36513.56 2 102.08 100-002 4637.44 5.39 243 12.58 1.5 97.84 100-003 2939.588.50 194 8.31 5 101.94 100-004 3603.33 6.94 188 11.56 7.5 115.72 100-0054122.74 6.06 355 7.46 3 65.28 100-006 2441.04 10.24 283 9.77 1.5 144.29100-007 2956.81 8.46 237 9.01 4 109.95 100-008 3107.86 8.04 259 9.46 4109.80 100-009 3507.21 7.13 309 12.68 1.5 130.43 100-010 5499.09 4.55270 9.92 15 65.09 100-011 5010.35 4.99 495 10.71 1.5 77.11 100-0126291.34 3.97 362 15.07 5 86.39 100-013 3680.45 6.79 249 12.42 3 121.75100-014 4918.55 5.08 289 14.54 2 106.65 100-015 7556.68 3.31 521 15.761.5 75.21 100-016 3031.10 8.25 191 10.13 5 120.51 100-017 4598.78 5.44332 14.25 3 111.79 100-018 5636.28 4.44 271 14.65 4 93.72 100-0196316.53 3.96 435 14.60 1.5 83.35 100-020 5933.57 4.21 573 12.70 2 77.19100-021 4716.13 5.30 287 12.75 3 97.54 100-022 6474.80 3.86 371 12.34 268.75 100-023 4255.72 5.87 310 9.94 0.75 84.21 100-024 6666.45 3.75 49511.73 3 63.45 100-025 5586.21 4.48 423 9.59 2 61.89 100-026 4278.71 5.84287 10.57 3 89.13 100-027 7541.99 3.31 347 13.79 3 65.97 100-028 3252.187.69 233 9.50 3 105.32 100-029 6730.23 3.71 443 11.66 2 62.51 100-0305578.20 4.48 546 9.19 1.5 59.42 100-031 9821.40 2.55 589 24.75 5 90.88100-032 4936.93 5.06 381 8.67 3 63.36 100-033 3913.08 6.39 296 10.76 299.14 100-034 5323.39 4.70 303 13.14 3 89.03 100-035 3740.84 6.68 3319.14 2 88.12 100-036 4568.89 5.47 275 12.60 4 99.47 100-037 5274.36 4.74299 13.49 1.5 92.24 100-038 4317.48 5.79 254 9.69 5 80.93 100-03910044.52 2.49 401 12.72 1.5 45.67 100-040 5447.91 4.59 392 10.54 1.569.79 100-041 4199.46 5.95 358 8.37 3 71.88 100-042 2404.47 10.40 2845.11 2 76.71 100-043 6742.96 3.71 397 12.50 5 66.85 100-044 5025.11 4.98302 14.44 4 103.65 100-045 3205.43 7.80 282 11.59 1.5 130.40 100-0464055.32 6.16 248 9.71 4 86.41 100-047 2522.47 9.91 207 11.42 5 163.24100-048 5008.86 4.99 370 14.01 2 100.92 100-049 3141.52 7.96 226 8.92 3102.38 100-050 5703.73 4.38 274 14.60 5 92.34 100-051 4610.93 5.42 29410.48 1.5 81.95 100-052 6876.95 3.64 366 13.82 5 72.49 100-053 4283.725.84 345 9.60 2 80.81

FIG. 25 shows a summary of fasted AUC_(0-∞) and Cmax observed in thepharmacokinetic study. The geometric mean (natural −log SD) for theAUC_(0-∞) is 4640 ng*hr/mL. The geometric mean (natural −log SD) for theCmax is 318 ng/mL.

FIG. 26 shows a summary of treatment-emergent adverse events (TEAE).There were four subjects observed with TEAEs, which constitutes 7.5% ofthe cohort. TEAE related to the rofecoxib treatment were observed in 2subjects, which constitutes 3.8% of the cohort. No subjects presentedwith serious TEAE or TEAE, which would lead to discontinuation of thestudy.

FIG. 27 shows mean fasted concentration of rofecoxib versus scheduledtime. A peak is observed between 2 hours and 5 hours after a singleadministration of the rofecoxib (TRM-201) formulation.

FIG. 28 shows analysis of AUC_(0-∞) and Cmax compared to historical dataderived from Schwartz, J. I., et al. Clin. Drug Invent. 2003, 23 (8):503-509. The rofecoxib (TRM-201) disclosed herein achieves largerAUC_(0-∞) and higher Cmax than historical data.

FIG. 29 shows a scatterplot of AUC_(0-∞) by age in fasted subjects. FIG.30 shows a scatterplot of Cmax by age in fasted subjects.

References for Example 4

-   Bresalier R S, Sandler R S, Quan H, et al. Cardiovascular events    associated with rofecoxib in a colorectal adenoma chemoprevention    trial. New Engl J Med 2005; 352:1092-102.-   Matthews C Z, Woolf E J, Matuszewski B K. Improved procedure for the    determination of rofecoxib in human plasma involving 96-well    solid-phase extraction and fluorescence detection. J Chromatogr A.    2002; 949(1-2):83-9.-   Schwartz J I, Larson P J, Porras A G, et al. Pharmacokinetic    evaluation of rofecoxib: comparison of tablet and suspension    formulations. Clin Drug Invest. 2003; 23(8):503-9.-   Tsoukas C, Eyster M E, Shingo S, et al. Evaluation of the efficacy    and safety of etoricoxib in the treatment of hemophilic arthropathy.    Blood. 2006; 107(5):1785-90.-   U.S. Food and Drug Administration. Analysis and recommendations for    agency action regarding nonsteroidal antiinflammatory drugs and    cardiovascular risk. J Pain Palliat Care Pharmacother. 2005;    19(4):83-97.-   VIOXX (rofecoxib) [package insert]. Merck & Co., Inc. Whitehouse    Station, N.J.; 2016. 26 p.

Example 5

Extrapolated PK Values for Dosages Less than 25 mg of Rofecoxib.

FIG. 31 shows extrapolated pharmacokinetic values for 17.5 mg and 20 mgof rofecoxib. For 17.5 mg of rofecoxib, the AUC_(0-∞) is 3248 h*ng/mLand Cmax is 222.6 ng/mL. For 20 mg of rofecoxib, the AUC_(0-∞) is 3712h*ng/mL and Cmax is 254.4 ng/mL. These values are extrapolated from thepharmacokinetic study of Example 4 based on results obtained from asingle administration of 25 mg of rofecoxib in healthy subjects, andassumes dose linearity across the dosage strengths.

Example 6 A Single-Dose, Open-Label, Phase 1, Four-Period CrossoverPharmacokinetic Study of TRM-201 (Rofecoxib) 12.5 mg, 17.5 mg, 20 mg and25 mg Administered to Healthy Subjects in a Fasting State, withComparison to Historical Pharmacokinetic Parameters of PreviouslyMarketed Rofecoxib (“TRM-201-PK-102” or “102 PK Study”) Introduction

TRM-201 (rofecoxib) was developed for the treatment of hemophilicarthropathy (HA). Rofecoxib is a cyclooxygenase-2 (COX-2) selective,non-steroidal anti-inflammatory drug (NSAID) with analgesic,anti-inflammatory, and anti-pyretic properties. At therapeuticconcentrations, rofecoxib inhibits COX-2 but not cyclooxygenase 1(COX-1). The U.S. Food and Drug Administration (FDA) first approvedrofecoxib for marketing in 1999, and rofecoxib was eventually approvedfor the following indications in adults: relief of the signs andsymptoms of osteoarthritis, relief of the signs and symptoms ofrheumatoid arthritis, management of acute pain in adults, treatment ofprimary dysmenorrhea, and acute treatment of migraine attacks with orwithout aura. The approved doses for osteoarthritis were 12.5 mg/day or25 mg/day, and the approved dose for rheumatoid arthritis was 25 mg/day.

The safety profile was established in over 17,000 patients in placebo-and active-controlled studies at therapeutic and supra-therapeuticdoses, with some patients having had exposure for up to 2 years. On 30Sep. 2004 Merck and Co., Inc. voluntarily withdrew rofecoxib from allmarkets worldwide following the observation of an increased risk ofserious adverse cardiovascular events compared to placebo in a long-termcontrolled clinical trial (Bresalier et al 2005).

In April 2005, FDA issued a memorandum concluding its Analysis andRecommendations for Agency Action regarding NSAIDs and cardiovascularrisk. Related to rofecoxib, FDA concluded in part (FDA 2005):

Along with the other approved COX-2 selective NSAIDs available at thetime (i.e., celecoxib, and valdecoxib), rofecoxib was associated with anincreased risk of serious adverse cardiovascular events compared toplacebo.

Data from large long-term controlled clinical trials that have includeda comparison of COX 2 selective and non-selective NSAIDs did not clearlydemonstrate that the COX-2 selective agents confer a greater risk ofserious adverse cardiovascular events than non-selective NSAIDs.

Along with the other approved COX-2 selective NSAIDs available at thetime (i.e., celecoxib, and valdecoxib), rofecoxib had demonstrated areduction in the incidence of gastrointestinal (GI) ulcers visualized atendoscopy compared to certain non-selective NSAIDs. Only rofecoxib hadbeen shown to reduce the risk of serious GI bleeding compared to anon-selective NSAID (naproxen) following chronic use.

Should a sponsor seek to resume marketing for rofecoxib, a supplementalnew drug application with revised labeling will be required. Thesupplemental application should specifically outline the sponsor'sproposal for revised labeling designed to provide for safe and effectiveuse of the drug in populations where the potential benefits of the drugmay outweigh potential risks, and all data and arguments that supportresumption of marketing.

In a two-part study focused on the efficacy of etoricoxib, another COX-2inhibitor, in patients with HA, (Tsoukas et al 2006), rofecoxib (19subjects) exhibited similar efficacy to etoricoxib (74 patients) in the6-month extension of the study (Part 2) for the primary endpoint(Patient Global Assessment of Arthropathy Pain) and the two secondaryendpoints (Patient Global Assessment of Arthropathy Disease Status andInvestigator Global Assessment of Arthropathy Disease Status). In thesix weeks of Part 1, etoricoxib provided clinically and statisticallysignificant improvement on all endpoints versus placebo (P<0.001),including the following additional endpoints: Patient's GlobalAssessment of Response to Therapy, Investigator's Assessment of Responseto Therapy, Patient Discontinuation Due to Lack of Efficacy, and AverageRescue Acetaminophen Usage per Day.

In view of preliminary evidence of efficacy of rofecoxib in treatingpain associated with HA, the associated reduction of risk in GI adverseevents (AEs) compared to nonselective NSAIDs, the comparability of riskof serious cardiovascular events with rofecoxib to comparably effectivedoses of nonselective NSAIDs, and the risks associated with the use ofopioids to treat pain in this patient population, the use of rofecoxibwill be evaluated for the treatment of HA.

Given that there have been no approved rofecoxib products availableglobally since September 2004, the first Phase I study under aninvestigational new drug (IND) application was a PK study(TRM-201-PK-101, as described in Example 4) in healthy volunteersdesigned to assess the PK profile of a 25-mg dose of TRM-201, forcomparison to published data for the previously marketed rofecoxib (seeExample 4). Top-line results from the combined dataset of Fastedsubjects from the PILOT, MAIN and FOOD-EFFECT portions of TRM-201-PK-101yielded significantly greater exposure to key PK parameters as comparedto historical data reported in literature. Based on this result and theneed to establish a scientific bridge in order “to rely on the systemicsafety findings of Vioxx” and “demonstrate the exposure of yourrofecoxib product is comparable to, or lower than, that of Vioxx”, thissecond PK study was conducted. The current study was designed toevaluate a single dose of TRM-201 at 12.5 mg, 17.5 mg, 20 mg and 25 mgin a four-period crossover design in 24 subjects in a fasted conditionto match the exposure to that of Vioxx. This study was designed to beevaluated along with the PK data from the fasted portion of theTRM-201-PK-101 study to select a dose comparable to the 25-mg dose ofpreviously marketed rofecoxib based on historical PK parameters.

Primary Objectives:

1. To evaluate key PK parameters of TRM 201 at doses of 12.5 mg 17.5 mg,20 mg and 25 mg in healthy subjects and use these data along with thedata from the TRM-201-PK-101 study to compare TRM-201 to historical PKparameters of previously marketed rofecoxib, all in a fasted state. Thekey PK parameters for rofecoxib were the following:

-   -   Area under the plasma concentration-time curve from time zero to        infinity (AUC_(0-∞))    -   Observed maximum plasma concentration (Cmax)

Secondary Objectives:

1. To assess the safety and tolerability of TRM-201 at doses of 12.5 mg,17.5 mg, 20 mg and 25 mg in healthy subjects.

2. To evaluate additional PK parameters of TRM-201 at doses of 12.5 mg,17.5 mg, 20 mg and 25 mg in healthy subjects and use these data alongwith the data from the TRM-201-PK-101 study to compare to historical PKparameters of previously marketed rofecoxib, all in a fasted stateincluding:

-   -   Time to observed maximum concentration (T_(max))    -   Apparent terminal elimination half-life (t_(1/2))

Study Population

A sufficient number of subjects were screened, and 24 subjects wereenrolled to ensure that at least 20 evaluable subjects complete thestudy. In order to mirror the population of subjects in the PK study(Schwartz et al. 2003) every effort was made to enroll subjects in thefollowing proportion: White or European American (80%), Black (20%). Ofthe White subjects enrolled, every effort was made to enrollapproximately 60% of the subjects who identify themselves as being ofHispanic or Latino ethnicity resulting in an overall percentageapproximately 48% Hispanic or Latino participants in the study. Subjectswere enrolled only if they met all the inclusion criteria and none ofthe exclusion criteria and all of the continuing eligibility criteria.Deviations from the inclusion and exclusion criteria were not allowed.

Inclusion Criteria:

-   -   1. The subject was male or female and was 18 to 60 years of age,        inclusive, at Screening. Similar numbers of male and female        subjects were enrolled.    -   2. The subject had a BMI at Screening of 18 to 32 kg/m²,        inclusive, with a minimum weight of 47 kg for women and 66 kg        for men and a maximum weight of 80 kg for women and 90 kg for        men.    -   3. The subject was not a smoker (or user of e-cigarettes).    -   4. The investigator considered the subject was in good general        health as determined by medical history, clinical laboratory        test results, vital sign measurements, 12-lead electrocardiogram        (ECG) results, and physical examination findings at Screening        and Check-in.    -   5. All female subjects had a negative pregnancy test at        Screening. Female subjects of childbearing potential also had a        negative pregnancy test at Check-in and were using an acceptable        method of birth control during the study (i.e., diaphragm with        spermicide, intrauterine device, condom with foam or vaginal        spermicide, oral contraceptives, or abstinence). Women who were        surgically sterile (i.e., hysterectomy, bilateral tubal ligation        or bilateral oophorectomy), or postmenopausal (defined as        amenorrhea for 12 consecutive months and documented serum        follicle-stimulating hormone level >40 IU/mL) were exempt from        the adequate contraception requirement.    -   6. The subject agreed to comply with all protocol requirements        as well as the particular requirements and specific Phase I unit        policies.    -   7. The subject provided written informed consent.

Exclusion Criteria:

-   -   1. The subject had a history of relevant drug allergy or food        allergy/sensitivity (e.g., allergy to rofecoxib or excipients of        TRM-201, allergy to other non-steroidal anti-inflammatory drugs        (NSAIDs), or gluten intolerance that could preclude consumption        of a standard clinic diet).    -   2. A female subject was pregnant or lactating.    -   3. The subject had a history of intolerance or hypersensitivity        to aspirin or any other NSAID.    -   4. The subject had a positive test result for hepatitis B        surface antigen, hepatitis C virus antibody, or human        immunodeficiency virus types 1 or 2 antibodies at Screening.    -   5. The subject had used any prescription (excluding hormonal        birth control) or over the counter medications (OTC) including        NSAIDs (e.g., ibuprofen, naproxen, and aspirin) as well as        herbal or nutritional supplements, within 14 days before the        study drug dosing. Subjects could have taken acetaminophen (up        to 2 g per day) in the 14 days prior to study drug dosing.    -   6. The subject had any clinically significant abnormalities        before dosing on Day 1 or had a history of disease, including:        uncontrolled or poorly controlled hypertension; asthma or        pulmonary disease; major cardiac ischemic symptoms, events, or        interventions such as angina pectoris, myocardial infarction,        acute coronary syndrome, decompensated congestive heart failure,        coronary stent or bypass; history of cerebrovascular ischemic        events (transient ischemic attack or stroke); major vascular        ischemic symptoms such as intermittent claudication or vascular        bypass or replacement surgery; significant cardiovascular,        gastrointestinal (GI), neurological, endocrine, or renal        disease; hepatic impairment; cholecystectomy; other condition        known to interfere with the absorption, distribution,        metabolism, or excretion of drugs; or clinically significant GI        events.    -   7. The subject had a history or presence of any clinically        significant abnormality in vital signs, ECG, or laboratory        tests, or had any medical or psychiatric condition that, in the        opinion of the investigator, could interfere with the study        procedures or compromise subject safety (assessed at Screening        and Check-in).    -   8. The subject was a cigarette smoker or had used nicotine or        nicotine-containing products (e.g., snuff, nicotine patch,        nicotine chewing gum, e-cigarettes) within 6 months before study        drug dosing.    -   9. The subject had a history of alcohol abuse or drug addiction        within the last year or consumes more than 1 unit (1 unit is        equal to approximately ½ pint [200 mL] of beer, 1 small glass        [100 mL] of wine, or 1 measure [25 mL] of spirits) of alcohol a        day. Alcohol was not allowed within 7 days before study drug        dosing.    -   10. The subject had a positive test result for drugs of abuse,        alcohol, or cotinine (indicating active current smoking) at        Screening.    -   11. The subject was a habitual and heavy coffee drinker (more        than 4 cups a day, 28 cups a week).    -   12. The subject was involved in strenuous activity or contact        sports within 24 hours before study drug dosing.    -   13. The subject had donated blood or blood products within 30        days before the dose of study drug in this study.    -   14. The subject had received study drug in another        investigational study within 30 days (or less than 5 half-lives        of the investigational agent) prior to dosing in this study.    -   15. The subject was not suitable for entry into the study, in        the opinion of the investigator.    -   16. The subject was an employee or family member of the        investigator or clinic staff.

Continuing Eligibility at Check-In

-   -   1. Females had a negative serum pregnancy test.    -   2. All subjects had a negative test results for drugs of abuse        and alcohol    -   3. Subjects had no significant changes in overall health status        since screening including the use of medications.    -   4. The subject was involved in strenuous activity or contact        sports within 24 hours before study drug dosing.

Subjects with test results which did not meet the aboveinclusion/exclusion criteria could have the relevant test repeated onceif it was thought to represent a laboratory error, a reversible,clinically insignificant intermittent condition, or was not consistentwith the subject's historical values. If inclusion/exclusion criteriawere not met after the repeat test, the subject was considered a screenfailure and was not enrolled in the study. Subjects were retested once.

Study Design

This was a single-center, open-label four-period crossover PK study ofTRM-201. The study included 24 subjects who received TRM-201 as a singledose of 12.5 mg, 17.5 mg, 20 mg and 25 mg to assess the PK of TRM-201 inhealthy volunteers under fasted conditions. Subjects were randomized toone of four treatment sequences. The PK data from the current studyalong with the data from the TRM-201-PK-101 study (Example 4) was usedto compare to historical pharmacokinetic parameters of previouslymarketed rofecoxib, all in a fasted state.

The subjects were screened in the 28 days before receiving the singledose of TRM-201 in the first period. Subjects checked in to the clinicon the day before dosing for Dosing Period 1, and their eligibility wasconfirmed. Subjects remained at the clinic from Check-In through thecompletion of the end of study (EOS) visit on Day 27 of Dosing Period 4.The total duration of the study was approximately 55 days.

After Check-In, subjects fasted overnight for at least 10 hours beforestudy drug administration. In the morning of the dosing day of Period 1,subjects were randomized to one of four treatment sequences:

-   -   Dosing Period 1: ADBC    -   Dosing Period 2: BACD    -   Dosing Period 3: CBDA    -   Dosing Period 4: DCAB

Where A=12.5 mg, B=17.5 mg, C=20 mg and D=25 mg

Regardless of the dosing sequence assigned, all subjects underwent thesame assessments, pre and post-dose.

In each of the four dosing periods, subjects fasted overnight for atleast 10 hours before study drug dosing. While fasting, subjects hadnothing to eat and only water to drink. Water was permitted as desired,except for the period between 1 hour before and 1 hour after study drugdosing (excepting as permitted for dosing). After the 2-hour PK bloodsample, subjects were allowed one 250-mL cup of clear apple juice. Afterthe 4-hour PK blood sample, subjects were served a light lunch.Following the light lunch, subjects received standardized mealsaccording to the clinic's standard procedures that were scheduled atconsistent times and at least 15 minutes before or 15 minutes after PKsampling time points. Blood was withdrawn for PK analysis at predefinedtime points. For each dosing period the last time point was 120 hoursafter dosing with study drug (Day 6). After the 120 hour PK sample, theEOP procedures was completed, subjects remained in-clinic for thein-between dose period day (Days 7, 14, and 21) and began the nextdosing period starting with an overnight fast for at least 10 hours onDay −1 of the subsequent dosing period. Pharmacokinetic and safetyendpoints were evaluated.

Rationale of Study Design

The subject matter disclosed herein relates to a scientific bridgebetween TRM-201 and the previously marketed rofecoxib in support of a505(b)(2) new drug application. Because there are presently noFDA-approved rofecoxib products commercially available globally withwhich to conduct a directly comparative bioavailability/bioequivalencestudy, the present study, along with the data from the TRM-201-PK-101study, was designed to provide PK data for a cross-study comparison to apublished study (Schwartz et al. 2003) that was submitted to FDA,accepted by FDA, and used in the approved package insert for rofecoxib.

The four doses of rofecoxib (12.5 mg, 17.5 mg, 20 mg and 25 mg) wereselected for this study to combine with the 25-mg dose data fromTRM-201-PK-101 to select a dose that is comparable to the 25-mg dose ofpreviously marketed rofecoxib because it is the anticipated maximumdaily dose for the treatment of HA. The data from the study by Schwartzet al. (2003) were chosen for comparison because they represent PK datagenerated with the labeled version of rofecoxib at 25 mg. Theeligibility criteria for this current PK study were selected to mirrorthe subject demographics and subgroups (gender, age, body mass index[BMI], race, and ethnicity) in both the TRM-201-PK-101 and Schwartzstudies. A validated bioanalytical method for rofecoxib was developedand used for the PK analyses.

Administration of Study Drug

Study drug was co-administered orally with approximately 250 mL of roomtemperature water, and up to an additional 250 mL of water was allowed,if necessary, to aid in swallowing the study drug. Study staff ensuredthat at least 250 ml of water was consumed with the dose of study drugand performed a hand and mouth check after dosing to ensure the tabletwas swallowed.

After fasting for at least 10 hours overnight (Table 19), subjects took,a single dose (1 tablet) of TRM 201 on the morning of Day 1 in each ofthe four Dosing Periods administered as described above and supervisedby clinic staff. During the period between 1 hour before and 1 hourafter study drug dosing, subjects drank only the water permitted forstudy drug administration.

Identity of Study Drug

The study drug, TRM-201, was an immediate-release tablet that contained12.5 mg rofecoxib, 17.5 mg rofecoxib, 20 mg rofecoxib or 25 mgrofecoxib. The 7.25-mm diameter tablets were off-white, round, anduncoated with no markings. TRM-201 tablets were for oral administration.

TRM-201 tablets contained the active ingredient rofecoxib (12.5 mg, 17.5mg, 20 mg or 25 mg) and inactive excipients. Each tablet contained thefollowing inactive excipients: croscarmellose sodium, hydroxypropylcellulose, lactose, magnesium stearate, microcrystalline cellulose, andyellow pigment. Table 18 shows the specific formulation of the tabletsused in the this study:

TABLE 18 Composition of Rofecoxib Tablets 25-mg Tablet 20-mg Tablet17.5-mg Tablet 12.5-mg Tablet % (w/w) % (w/w) % (w/w) % (w/w) per mg perper mg per per mg per per mg per Components tablet tablet tablet tablettablet tablet tablet tablet Intragranular Rofecoxib^(a) 12.50 25.0 10.0020.0 8.75 17.5 6.25 12.5 Lactose monohydrate 39.85 79.7 41.10 82.241.725 83.45 42.975 85.95 Microcrystalline cellulose 39.85 79.7 41.1082.2 41.725 83.45 42.975 85.95 Hydroxypropylcellulose 3.00 6.0 3.00 6.003.00 6.0 3.00 6.0 Croscarmellose sodium 2.00 4.0 2.00 4.0 2.00 4.0 2.004.0 Pigment blend yellow 0.30 0.6 0.30 0.6 0.30 0.6 0.30 0.6 WaterNA^(b) NA^(b) NA^(b) NA^(b) NA^(b) NA^(b) NA^(b) NA^(b) ExtragranularCroscarmellose sodium 2.00 4.0 2.00 4.0 2.00 4.0 2.00 4.0 Magnesiumstearate 0.50 1.0 0.50 1.0 0.50 1.0 0.50 1.0 Totals 100.00 200.0 100.00200.0 100.00 200.0 100.00 200.0 ^(a)Note that the amount of rofecoxibmay be adjusted for purity and moisture content. An adjustment will bemade to the amounts of lactose monohydrate and microcrystallinecellulose used to maintain tablet weight. ^(b)Water for granulation isremoved upon drying of the wet mass.

TABLE 19 Schedule of events In-clnic between Dosing Periods 1, 2, 3 and4 Phase Screening Check-in -period day Pharmacokinetic Sampling EOP/EOSPeriod 1 Days −28 to −2 −1 NA 1 2 3 4 5 6 Period 2 Days 7 8 9 10 11 1213 Period 3 Days 14 15 16 17 18 19 20 Period 4 Days 21 22 23 24 25 26 27Informed consent X Demographics X Medical history X X Viral serology XSerum follicle-stimulating X hormone (females only) Admission to clinicX Serum pregnancy test X X X (females only) Urine drug screen X X(including alcohol and cotinine) Clinical laboratory testing X X X(blood/urine) Height, weight, and body X weight weight mass index ONLYONLY Physical examination^(a) X X X (EOS ONLY) Vital signmeasurements^(b) X X X X X X X X X 12-Lead ECG assessment^(c) X X X X(EOS ONLY) Eligibility assessment X X (initial and continuing) Studymeal schedule^(d) X X X X X X X X Study drug administration^(e) XPharmacokinetic sample X X X X X collection Adverse event assessment X XX X X X X Prior or concomitant X X X X X X X X medication assessmentDischarge from clinic X (EOS ONLY) Abbreviations: ECG,electrocardiogram; EOP, end of period; EOS, end of study. Note: Theorder of procedures on each day followed the order of presentation inTable 19 (top to bottom). When procedures overlapped or occurred at thesame time point, all blood sampling followed vital signs or ECGs, and PKsampling was timed to occur last and as close to the scheduled timewindow as possible. Timings of PK blood sampling and electrocardiogramassessments were calculated from time “0”, the time of study drugdosing. ^(a)A complete physical examination was performed at Screening(at minimum, assessment of skin, head, ears, eyes, nose, throat, neck,thyroid, lungs, heart, cardiovascular, abdomen, lymph nodes, andmusculoskeletal system/extremities). A brief physical examination wasperformed at Check-In and EOS (at minimum, assessment of skin, lungs,cardiovascular system, and abdomen). Interim physical examinations wasperformed at the discretion of the investigator, if necessary, toevaluate adverse events or clinical laboratory abnormalities. ^(b)Vitalsigns included systolic and diastolic blood pressure, pulse rate,respiratory rate, and oral body temperature, after the subject had beenseated for at least 5 minutes. On Day 1 of each Dosing Period, vitalsigns were measured within 120 minutes before study drug dosing and atthe 2-hour, 3-hour and 7.5-hour post dose time points. At these timepoints (2 h, 3h and 7.5 h) only systolic and diastolic blood pressure,pulse rate and respiratory rate were assessed. On Days 2 through 6 ofeach dosing period, vital signs were assessed within 15 minutes beforethe first PK blood sample of the day. ^(c)After the subject had been inthe supine position for at least 5 minutes, single 12-lead ECGrecordings were taken at Screening and Check-in, and on Dosing Day 1pre-dose and at the 2-hour and 3-hour post-dose time point for each ofthe four dosing periods and at EOS. ^(d)The fasting period began at theday of Check-In and on each in-clinic between Dosing Period Day (Days 7,14, 21) for at least 10 hours overnight before study drug administrationfor each period. ^(e)Study drug was administered after vital signmeasurements has been completed. Study drug was administered with −250mL of room temperature water. Up to an additional −250 mL of water wereallowed, if necessary, to aid in swallowing the study drug. Subjectsmaintained an upright position (seated or standing) for at least 4 hoursafter dosing. The dosing for each Dosing Period for each subjectoccurred at least 7 days after Period-1 dosing.

Pharmacokinetic Procedures, Assessments, and Endpoints

The time points and windows for PK blood sampling were presented inTable 20 below. For each sample, approximately 3 mL of blood were drawn.The samples were obtained by a straight stick or via an in-dwellingintravenous (IV) catheter in a forearm vein. Additional details for thecollection, processing, storage, and shipping of PK samples wereprovided in the study manual.

TABLE 20 Times and Windows for Dosing Period 1, 2, 3 and 4Pharmacokinetic Blood Sampling Units of Time Minutes Hours Timepoint0^(a) 15 30 45 1 1.5 2 3 4 5 6 7.5 9 12 15 18 21 24 27 30 33 36 39 42 4852 60 72 96 120 Window ±5 min ±10 min ±15 min ±30 min ±60 min (min)Abbreviation: min; minutes. ^(a)The blood sample for time 0 were takenwithin 1 hour before dosing with study drug.

Pharmacokinetic samples will be analyzed using a validated assay forrofecoxib in human plasma. Assay results and validation details will beprovided in a separate bioanalytical report. The following PK parametersfor rofecoxib will be calculated as primary endpoints using standardnoncompartmental methods: AUC_(0-∞) and C_(max). Secondary endpointsinclude T_(max), and t_(1/2). Additional PK parameters (e.g., CL/F, andV_(d)/F) will also be calculated using standard noncompartmentalmethods.

Safety Assessments

The timing and frequency of all safety assessments was listed in theschedule of events (Table 19). Safety and tolerability includedmonitoring and recording of AEs, clinical laboratory assessments(hematology, serum chemistry, and urinalysis), vital sign measurements,12-lead ECG assessments, and physical examination findings. For allsafety assessments, the investigator determined whether results wereclinically significant, which was defined as any variation in a resultthat had medical relevance and could have resulted in an alteration inmedical care (e.g., active observation, diagnostic measures, ortherapeutic measures). If clinical significance was noted, the resultand reason for significance were documented. Any abnormal laboratorytest results (hematology, clinical chemistry, or urinalysis) or othersafety assessments (e.g., ECGs, vital sign measurements), includingthose that worsen from baseline, felt to be clinically significant inthe medical and scientific judgment of the investigator were to berecorded as AEs or SAEs.

Adverse Events

Definitions of Adverse Events

The investigator was responsible for reporting all AEs that wereobserved or reported during the study, regardless of their relationshipto study drug or their clinical significance. If there was any doubt asto whether a clinical observation was an AE, the event was reported. AnAE was defined as any untoward medical occurrence in a subject enrolledinto this study regardless of its causal relationship to study drug.Subjects were instructed to contact the investigator at any time afterenrollment if any symptoms developed. A treatment-emergent AE (TEAE) wasdefined as any event not present before exposure to study drug or anyevent already present that worsens in either intensity or frequencyafter exposure to study drug.

Serious Adverse Events (SAE)

An SAE was defined as any event that:

-   -   resulted in death    -   was immediately life threatening    -   required inpatient hospitalization or prolongation of existing        hospitalization    -   resulted in persistent or significant disability/incapacity    -   was a congenital anomaly/birth defect

Important medical events that did not result in death, were not lifethreatening, or did not require hospitalization were considered SAEswhen, based upon appropriate medical judgment, they jeopardized thesubject or required medical or surgical intervention to prevent one ofthe outcomes listed in this definition. Examples of such medical eventsincluded allergic bronchospasm requiring intensive treatment in anemergency room or at home, blood dyscrasias or convulsions that did notresult in inpatient hospitalization, or the development of drugdependency or drug abuse.

Comparability of TRM-201 with Previously Marketed Rofecoxib

Consistent with the data of Schwartz et al. (2003) and TrialTRM-201-PK-101, the total sample size of 20 evaluable subjects wasconsidered sufficient for the objectives of the study. Power wascomputed as the probability that the upper limit of a 90% CI for thegeometric mean ratio (GMR=observed geometric mean from this trialdivided by the historical control value) for these parameters fell below1.25. Observed natural-log-scale between-subject SDs from TrialTRM-201-PK-101 were approximately 0.31 and 0.30 for AUC_(0-∞) and Cmax,respectively; within-subject SD's from the food effect sub-study were0.10 and 0.12, respectively. Geometric mean AUC and Cmax from the 25 mgformulation in TRM-201-PK-101 were 4685 ng·hr/ml and 320 ng/ml,respectively. These were higher than the corresponding values fromSchwartz et al. (2003), which were 3799 and 217, respectively. Sincerofecoxib PK was found to be linear across the 12.5 to 50-mg dose range(Vioxx Package Insert), the 20 mg formulation in this trial wasestimated to have AUC-3741 and Cmax-266; for the 17.5 mg formulation,AUC-3276 and Cmax-238.

The primary analysis model for data from this trial included data fromthis trial and that from the 25-mg dose from TRM-201-PK-101 (fastedresults only), which were combined via mixed model repeated measuresanalysis (MMRM) in order to maximize the precision of the estimates. AnMMRM analysis on natural log scale was simulated for the 25-mg dose(N=50) data using the between-subject SD of 0.31 from TRM-201-PK-101 andfor the estimated 25-mg and 20-mg data that N=20 subjects were expectedto yield in this study. The purpose of this simulation was to estimatethe SD for the least squares natural log scale mean for the 20-mg dose.This SD estimate was identical for the 17.5-mg dose since that expectedleast squares mean was a constant shift lower than that for 20 mg;hence, it sufficed to run the simulation only once. The subject effectdata expected for this study was simulated from the back-calculatedvariance of the between-subject mean effect (Var(between-subject-mean)=SDbetween{circumflex over( )}2−SDwithin{circumflex over ( )}2). For the maximum between- andwithin-SD's 0.31 and 0.12, 1000 simulations yielded an effective SD of0.21 for the least squares mean of 20 mg, which was used for thefollowing power calculations.

Note that if this combined analysis of both PK trials were not carriedout, then the comparison of AUC and Cmax from each dose in this trialwould be based on only N=20 subjects using the between-subject SD (˜0.3or 0.31). The MMRM analysis of both trials combined leverages the 25 mgvs 20 mg (and 25 mg vs 17 mg, and 25 mg vs 12.5 mg) difference from thistrial which was based on the within-subject SD ˜0.10 subtracted from thepooled estimate of the 25 mg AUC or Cmax from N=70 subjects using thebetween-subject SD. This yields an effective SD for each of the 20 mg,17.5 mg, and 12.5 mg comparisons to the historic control value.

Power was computed as the probability that the upper limit of a 90% CIfor the geometric mean ratio (GMR=observed geometric mean from thistrial divided by the historical control value) for these parameters fellbelow 1.25. Assuming a natural-log-scale SD equal to 0.21, N=20 hadapproximately 81% power if the TRUE underlying geometric mean ratio(GMR)=1.10, and approximately 90% power if the TRUE underlying GMR=1.08.The maximum OBSERVED GMR that would reject the null hypothesis is 1.14.Table 21 shows AUC_(0-∞) and C_(max) geometric mean values associatedwith the ratios computed from the effective SD=0.21.

TABLE 21 Power Estimates for Comparability between TRM-201 andPreviously Marketed Rofecoxib Geometric Mean Ratios Maximum OBS.Fold-Increase for 1.15^(a) Comparability TRUE Fold-Incr. for ~80% power1.11^(a) TRUE Fold-Incr. for ~90% power 1.08^(a) Historical mean 1.25Times PK Geometric value from the historical Parameter Parameter MeansSchwartz (2003) mean value C_(max) Max. OBS. Geo.Mean for 250 217C_(max) 25 mg 271 Comparability TRUE Geo.Mean for ~80% power 241 217 271TRUE Geo.Mean for ~90% power 234 217 271 AUC_(0-∞) Max. OBS.Geo. Meanfor 4369 3799 AUC_(0-∞) 4749 Comparability 25 mg TRUE Geo.Mean for ~80%power 4217 3799 4749 TRUE Geo.Mean for ~90% power 4103 3799 4749 C_(max)Max. OBS.Geo. Mean for 281 244 C_(max) 12.5 mg 305 Comparabilitydose-adjusted TRUE Geo.Mean for ~80% power 271 244 to 25 mg 305 TRUEGeo.Mean for ~90% power 264 244 305 Abbreviations; Geo.Mean, geometricmean; Incr. increase; Max., maximum; OBS., observed. ^(a)Fold-increaseexpressed relative to the historical mean value

Analysis Sets

The PK analysis set included subjects who receive a single dose ofTRM-201 and had sufficient concentration data to support accurateestimation of at least one PK parameter. Subjects who experiencevomiting within 2 times the median T_(max) (approximately 6 hours) afterstudy drug dosing will be excluded from the PK analysis. The safetyanalysis set will include all subjects who received at least 1 dose ofstudy drug.

Description of Subgroups to be Analyzed

The relationship of AUC_(0-∞) and C_(max) to age and to BMI were eachassessed via scatter plots and correlation coefficients. If appropriate,additional modeling of those relationships may be carried out. Summarystatistics for AUC_(0-∞) and C_(max) were provide by gender, agecategories (divided into tertiles), race categories, and ethnicitycategories.

Statistical Analysis Methodology

For categorical variables, frequencies and percentages were presented.Continuous variables were summarized using descriptive statistics(number of subjects, mean, median, SD, minimum, maximum, geometric mean,natural-log-scale SD). Baseline demographic and background variableswere summarized overall for all subjects. The number of subjects whoenrolled in the study and the number and percentage of subjects whocompleted the study were presented. Frequency and percentage of subjectswho withdrew or discontinued from the study, and the reason forwithdrawal or discontinuation, was also summarized. Statistical analysiswas performed using SAS software Version 9.4 or later. Continuousvariables were summarized using the mean, the standard deviation,median, minimum value, and maximum value. Categorical variables weresummarized using frequency counts and percentages. Data were listed indata listings.

Analysis of Pharmacokinetic Endpoints

Individual plasma concentrations for rofecoxib and PK sampling timedeviation data will be presented in a data listing. Plasma concentrationdata will be summarized by time point using the following descriptivestatistics: number of subjects, arithmetic mean, SD, coefficient ofvariation (CV), geometric mean, natural-log-scale SD, geometric CV,median, minimum, and maximum. Individual plasma concentration versusactual time profiles were presented on both linear and semilogarithmicscales. Additionally, arithmetic mean concentration versus scheduledtime profiles were presented on linear scales and geometric means onsemilogarithmic scales.

The PK parameters of rofecoxib were analyzed based on the actualsampling times. All parameters were calculated using the Phoenix®WinNonlin® version 6.4 or higher (Certara USA Inc., Princeton, N.J.) orSAS® version 9.3 or higher (SAS Institute Inc., Cary, N.C.). Theindividual PK parameters were presented in data listings. Summarystatistics for the primary PK endpoints, AUC_(0-∞) and C_(max), includedn, arithmetic mean, CV, SD, geometric mean, natural-log-scale SD,median, minimum, and maximum, along with the associated 90% CI computedon the natural-log-scale and back-transformed to the originalmeasurement scale. The GMR to historical control values and associated90% CIs were computed on log scale and back-transformed to the ratioscale; the reference values are from Schwartz et al. (2003): 3799ng·hr/mL and 217 ng/mL for AUC_(0-∞) and Cmax, respectively.

The primary hypotheses for both AUC_(0-∞) and C_(max) for each of the17.5 mg and 20 mg doses (tested via step-down approach: AUC followed byCmax for the 17.5 mg dose, followed by AUC and Cmax for the 20 mg dose)were:

-   -   Null Hypothesis: the TRUE underlying GMR (new formulation versus        historical control) was at least 1.25    -   Alternative Hypothesis: the TRUE underlying GMR (new formulation        versus historical control) was less than 1.25

These null hypotheses were each tested via comparing to 1.25 the upperlimit of a 90% CI for the geometric mean computed on thenatural-log-scale and back-transformed to the original scale. If theupper 90% CI lied below 1.25 times the historical control geometric meanvalue, the null hypothesis would have been rejected, and the alternativehypothesis would have been concluded. The AUC_(0-∞) and C_(max) nullhypotheses needed to be rejected to support a conclusion that the newformulation was sufficiently similar to the formulation that yielded thehistorical control data. Sensitivity analyses will be carried outseparately for AUC_(0-∞) and C_(max) using age- and race-adjustedgeometric means that match the mean age and race distribution of thehistorical control data. Secondary analyses similar to the primary werecarried out in comparison to a lower limit of 0.8 times the respectivehistorical control values.

The T_(max) was summarized by n, arithmetic mean, CV, SD, median,minimum, maximum, and 90% CI for the median via normal approximation.Apparent t_(1/2) was summarized by n, arithmetic mean, CV, SD, harmonicmean, jack-knife SD, median, minimum, and maximum. The 90% CI forharmonic mean was computed on the inverse scale and back-transformed tothe actual scale. The 90% CIs for median T_(max) and harmonic meant_(1/2) was compared to their respective historical control values. Inaddition to the proposed statistical approach to calculate the maximumobserved geometric mean ratio for the primary PK parameters using thetraditional bioequivalence reference range of 1.25, an alternativeapproach considered incorporating the variability in the PK parametersobserved in the reference Schwartz et al. (2003) study. The results forthe maximum observed geometric mean ratio for AUC_(0-∞) and C_(max) thatwould yield 90% CI<1.33 were similar to those of the proposed approach.Summary statistics for the secondary PK endpoints, including apparentplasma clearance (CL/F) and apparent volume of distribution (V_(d)/F)included n, arithmetic mean, SD, CV, geometric mean, natural-log-scaleSD, median, minimum, maximum, along with the associated 90% CI computedon the natural-log-scale and back-transformed to the originalmeasurement scale, as appropriate. An exploratory analysis was carriedout to estimate the dose that yielded values of AUC and Cmax equal tothose observed in the Schwartz (2003) paper. This analysis was carriedout via a linear regression fit in the MMRM analysis of thelog-transformed observations across the 12.5 to 25 mg range of doses inthis study.

Analysis of Safety Endpoints

All safety data were summarized. The incidence of adverse events waspresented by the MedDRA system organ class and preferred term,relationship to the test article, and severity. Descriptive statisticsof clinical laboratory results and vital signs were presented, as wellas summaries of changes from baseline (from the Check-in visit(s)) andof clinically notable values. All AE data were presented in a datalisting TEAEs were summarized overall, as well as by severity andrelationship to study drug. Serious AEs and AEs leading todiscontinuation of study drug were also presented in the data listingsand summarized. Actual values and changes from Baseline for clinicallaboratory test results, vital sign measurements, and 12-lead ECGresults were summarized at each time point using descriptive statistics(number of subjects, mean, SD, median, minimum, and maximum).

Results for Example 6

As shown in the summary of subjects in FIG. 32, 24 subjects wereadministered TRM-201 and all subjects completed the study. The medianage of the tested demographic is 49 years old with approximately 50%males and females as shown in FIG. 33. The subjects also included 5black or African-American subjects and 12 Hispanic or Latino subjects.FIG. 34 shows that the median body mass index (BMI) of the tested cohortwas 26.95 kg/m².

FIG. 35 shows demographic and baseline characteristics of the cohorttested in the pharmacokinetics (PK) study. FIG. 36 shows demographic andbaseline characteristics of BMI indicator in PK study. FIGS. 37-46 showthe summary of fasted plasma rofecoxib concentration (ng/mL) acrossvarious time points 0 hours and 120 hours following 12.5 mg, 17.5 mg, 20mg, or 25 mg of TRM-201 administration for the 102 PK study. As shown inFIGS. 37 and 38, the arithmetic mean plasma concentration for 12.5 mg ofTRM-201 at 15 minutes is 1.03 ng/ml and the geometric mean is 0.529ng/ml. The arithmetic mean plasma concentration for 17.5 mg of TRM-201at 15 minutes is 2.42 mg/ml and the geometric mean is 0.669 ng/ml. Thearithmetic mean plasma concentration for 20 mg of TRM-201 at 15 minutesis 5.75 ng/ml and the geometric mean is 1.16 ng/ml. The arithmetic meanplasma concentration for 25 mg of TRM-201 at 15 minutes is 5.63 ng/mland the geometric mean is 1.37 ng/ml. The arithmetic mean plasmaconcentration for 12.5 mg of TRM-201 at 45 minutes is 56.8 ng/ml and thegeometric mean is 33.9 ng/ml. The arithmetic mean plasma concentrationfor 17.5 mg of TRM-201 at 45 minutes is 93.0 mg/ml and the geometricmean is 51.6 ng/ml. The arithmetic mean plasma concentration for 20 mgof TRM-201 at 45 minutes is 121 ng/ml and the geometric mean is 72.6ng/ml. The arithmetic mean plasma concentration for 25 mg of TRM-201 at45 minutes is 159 ng/ml and the geometric mean is 97.6 ng/ml.

FIG. 47 shows a summary of fasted AUC_(0-∞) and C_(max) values for the101-PK (Example 4) and 102-PK (Example 6) studies, combining thoseresults for the 25 mg of TRM-201 dosage across the 101-PK and 102-PKstudies. The arithmetic mean AUC_(0-∞) for 12.5 mg of TRM-201 is 2010ng·hr/mL. The geometric mean AUC_(0-∞) for 12.5 mg of TRM-201 is 1880ng·hr/mL. The arithmetic mean AUC_(0-∞) for 17.5 mg of TRM-201 is 3290ng·hr/mL. The geometric mean AUC_(0-∞) for 17.5 mg of TRM-201 is 3110ng·hr/mL. The arithmetic mean AUC_(0-∞) for 20 mg of TRM-201 is 3750ng·hr/mL. The geometric mean AUC_(0-∞) for 20 mg of TRM-201 is 3550ng·hr/mL. The arithmetic mean AUC_(0-∞) for 25 mg of TRM-201 is 4810ng·hr/mL. The geometric mean AUC_(0-∞) for 25 mg of TRM-201 is 4590ng·hr/mL. The arithmetic mean C_(max) for 12.5 mg of TRM-201 is 151ng/mL. The geometric mean C_(max) for 12.5 mg of TRM-201 is 144 ng/mL.The arithmetic mean C_(max) for 17.5 mg of TRM-201 is 236 ng/mL. Thegeometric mean C_(max) for 17.5 mg of TRM-201 is 224 ng/mL. Thearithmetic mean C_(max) for 20 mg of TRM-201 is 277 ng/mL. The geometricmean C_(max) for 20 mg of TRM-201 is 259 ng/mL. The arithmetic meanC_(max) for 25 mg of TRM-201 is 336 ng/mL. The geometric mean C_(max)for 25 mg of TRM-201 is 325 ng/mL.

FIG. 48 shows a summary of fasted AUC_(0-∞) for the 102 PK study only.The arithmetic mean AUC_(0-∞) for 12.5 mg of TRM-201 is 2010 ng·hr/mL.The geometric mean AUC_(0-∞) for 12.5 mg of TRM-201 is 1880 ng·hr/mL.The arithmetic mean AUC_(0-∞) for 17.5 mg of TRM-201 is 3290 ng·hr/mL.The geometric mean AUC_(0-∞) for 17.5 mg of TRM-201 is 3110 ng·hr/mL.The arithmetic mean AUC_(0-∞) for 20 mg of TRM-201 is 3750 ng·hr/mL. Thegeometric mean AUC_(0-∞) for 20 mg of TRM-201 is 3550 ng·hr/mL. Thearithmetic mean AUC_(0-∞) for 25 mg of TRM-201 is 4630 ng·hr/mL. Thegeometric mean AUC_(0-∞) for 25 mg of TRM-201 is 4490 ng·hr/mL. FIG. 48also shows values for two model projections (calculated via an MMRMmodel) of AUC_(0-∞) geometric means across dosages.

FIG. 49 shows a summary of fasted C_(max) for the 102 PK study only. Thearithmetic mean C_(max) for 12.5 mg of TRM-201 is 151 ng/mL. Thegeometric mean C_(max) for 12.5 mg of TRM-201 is 144 ng/mL. Thearithmetic mean C_(max) for 17.5 mg of TRM-201 is 236 ng/mL. Thegeometric mean C_(max) for 17.5 mg of TRM-201 is 224 ng/mL. Thearithmetic mean C_(max) for 20 mg of TRM-201 is 277 ng/mL. The geometricmean C_(max) for 20 mg of TRM-201 is 259 ng/mL. The arithmetic meanC_(max) for 25 mg of TRM-201 is 349 ng/mL. The geometric mean C_(max)for 25 mg of TRM-201 is 341 ng/mL.

FIG. 50 shows a summary of fasted AUC_(0-∞) and C_(max) by gender forthe 102 PK study only for 12.5 mg of TRM-201. For males, the arithmeticmean AUC_(0-∞) is 1750 ng·hr/mL and the arithmetic mean C_(max) is 132ng/mL. For males, the geometric mean AUC_(0-∞) is 1580 ng·hr/mL and thegeometric mean C_(max) is 127 ng/mL. For females, the arithmetic meanAUC_(0-∞) is 2240 ng·hr/mL and the arithmetic mean C_(max) is 168 ng/mL.For females, the geometric mean AUC_(0-∞) is 2170 ng·hr/mL and thegeometric mean C_(max) is 160 ng/mL.

FIG. 51 shows a summary of fasted AUC_(0-∞) and C_(max) by gender forthe 102 PK study only for 17.5 mg of TRM-201. For males, the arithmeticmean AUC_(0-∞) is 2860 ng·hr/mL and the arithmetic mean C_(max) is 201ng/mL. For males, the geometric mean AUC_(0-∞) is 2710 ng·hr/mL and thegeometric mean C_(max) is 196 ng/mL. For females, the arithmetic meanAUC_(0-∞) is 3650 ng·hr/mL and the arithmetic mean C_(max) is 266 ng/mL.For females, the geometric mean AUC_(0-∞) is 3490 ng·hr/mL and thegeometric mean C_(max) is 251 ng/mL.

FIG. 52 shows a summary of fasted AUC_(0-∞) and C_(max) by gender forthe 102 PK study only for 20 mg of TRM-201. For males, the arithmeticmean AUC_(0-∞) is 3130 ng·hr/mL and the arithmetic mean C_(max) is 234ng/mL. For males, the geometric mean AUC_(0-∞) is 2940 ng·hr/mL and thegeometric mean C_(max) is 224 ng/mL For females, the arithmetic meanAUC_(0-∞) is 4270 ng·hr/mL and the arithmetic mean C_(max) is 314 ng/mL.For females, the geometric mean AUC_(0-∞) is 4160 ng·hr/mL and thegeometric mean C_(max) is 293 ng/mL.

FIG. 53 shows a summary of fasted AUC_(0-∞) and C_(max) by gender forthe 102 PK study only for 25 mg of TRM-201. For males, the arithmeticmean AUC_(0-∞) is 4080 ng·hr/mL and the arithmetic mean C_(max) is 302ng/mL. For males, the geometric mean AUC_(0-∞) is 3940 ng·hr/mL and thegeometric mean C_(max) is 298 ng/mL. For females, the arithmetic meanAUC_(0-∞) is 5090 ng·hr/mL and the arithmetic mean C_(max) is 388 ng/mL.For males, the geometric mean AUC_(0-∞) is 5020 ng·hr/mL and thegeometric mean C_(max) is 382 ng/mL.

FIG. 54 shows a summary of fasted AUC_(0-∞) and C_(max) by age for the102 PK study only for 12.5 mg of TRM-201. For 18-40 years, thearithmetic mean AUC_(0-∞) is 1680 ng·hr/mL and the arithmetic meanC_(max) is 164 ng/mL. For 18-40 years, the geometric mean AUC_(0-∞) is1570 ng·hr/mL and the geometric mean C_(max) is 156 ng/mL. For 41-52years, the arithmetic mean AUC_(0-∞) is 2090 ng·hr/mL and the arithmeticmean C_(max) is 140 ng/mL. For 41-52 years, the geometric mean AUC_(0-∞)is 1880 ng·hr/mL and the geometric mean C_(max) is 133 ng/mL. For 53-60years, the arithmetic mean AUC_(0-∞) is 2270 ng·hr/mL and the arithmeticmean C_(max) is 150 ng/mL. For 53-60 years, the geometric mean AUC_(0-∞)is 2240 ng·hr/mL and the geometric mean C_(max) is 143 ng/mL.

FIG. 55 shows a summary of fasted AUC_(0-∞) and C_(max) by age for the102 PK study only for 17.5 mg of TRM-201. For 18-40 years, thearithmetic mean AUC_(0-∞) is 2820 ng·hr/mL and the arithmetic meanC_(max) is 237 ng/mL. For 18-40 years, the geometric mean AUC_(0-∞) is2750 ng·hr/mL and the geometric mean C_(max) is 229 ng/mL. For 41-52years, the arithmetic mean AUC_(0-∞) is 3520 ng·hr/mL and the arithmeticmean C_(max) is 232 ng/mL. For 41-52 years, the geometric mean AUC_(0-∞)is 3160 ng·hr/mL and the geometric mean C_(max) is 213 ng/mL. For 53-60years, the arithmetic mean AUC_(0-∞) is 3510 ng·hr/mL and the arithmeticmean C_(max) is 239 ng/mL. For 53-60 years, the geometric mean AUC_(0-∞)is 3470 ng·hr/mL and the geometric mean C_(max) is 230 ng/mL.

FIG. 56 shows a summary of fasted AUC_(0-∞) and C_(max) by age for the102 PK study only for 20 mg of TRM-201. For 18-40 years, the arithmeticmean AUC_(0-∞) is 3580 ng·hr/mL and the arithmetic mean C_(max) is 308ng/mL. For 18-40 years, the geometric mean AUC_(0-∞) is 3420 ng·hr/mLand the geometric mean C_(max) is 289 ng/mL. For 41-52 years, thearithmetic mean AUC_(0-∞) is 3730 ng·hr/mL and the arithmetic meanC_(max) is 262 ng/mL. For 41-52 years, the geometric mean AUC_(0-∞) is3360 ng·hr/mL and the geometric mean C_(max) is 242 ng/mL. For 53-60years, the arithmetic mean AUC_(0-∞) is 3940 ng·hr/mL and the arithmeticmean C_(max) is 260 ng/mL. For 53-60 years, the geometric mean AUC_(0-∞)is 3880 ng·hr/mL and the geometric mean C_(max) is 249 ng/mL.

FIG. 57 shows a summary of fasted AUC_(0-∞) and C_(max) by age for the102 PK study only for 25 mg of TRM-201. For 18-40 years, the arithmeticmean AUC_(0-∞) is 4140 ng·hr/mL and the arithmetic mean C_(max) is 366ng/mL. For 18-40 years, the geometric mean AUC_(0-∞) is 4050 ng·hr/mLand the geometric mean C_(max) is 356 ng/mL. For 41-52 years, thearithmetic mean AUC_(0-∞) is 4810 ng·hr/mL and the arithmetic meanC_(max) is 326 ng/mL. For 41-52 years, the geometric mean AUC_(0-∞) is4580 ng·hr/mL and the geometric mean C_(max) is 321 ng/mL. For 53-60years, the arithmetic mean AUC_(0-∞) is 4940 ng·hr/mL and the arithmeticmean C_(max) is 354 ng/mL. For 53-60 years, the geometric mean AUC_(0-∞)is 4880 ng·hr/mL and the geometric mean C_(max) is 347 ng/mL.

FIG. 58 shows a summary of fasted AUC_(0-∞) and C_(max) by race for the102 PK study only for 12.5 mg of TRM-201. For Black or African-Americansubjects, the arithmetic mean AUC_(0-∞) is 1660 ng·hr/mL and thearithmetic mean C_(max) is 143 ng/mL. For Black or African-Americansubjects, the geometric mean AUC_(0-∞) is 1590 ng·hr/mL and thegeometric mean C_(max) is 142 ng/mL. For White subjects, the arithmeticmean AUC_(0-∞) is 2110 ng·hr/mL and the arithmetic mean C_(max) is 153ng/mL. For White subjects, the geometric mean AUC_(0-∞) is 1960 ng·hr/mLand the geometric mean C_(max) is 144 ng/mL.

FIG. 59 shows a summary of fasted AUC_(0-∞) and C_(max) by race for the102 PK study only for 17.5 mg of TRM-201. For Black or African-Americansubjects, the arithmetic mean AUC_(0-∞) is 2840 ng·hr/mL and thearithmetic mean C_(max) is 217 ng/mL. For Black or African-Americansubjects, the geometric mean AUC_(0-∞) is 2800 ng·hr/mL and thegeometric mean C_(max) is 211 ng/mL. For White subjects, the arithmeticmean AUC_(0-∞) is 3400 ng·hr/mL and the arithmetic mean C_(max) is 241ng/mL. For White subjects, the geometric mean AUC_(0-∞) is 3200 ng·hr/mLand the geometric mean C_(max) is 228 ng/mL.

FIG. 60 shows a summary of fasted AUC_(0-∞) and C_(max) by race for the102 PK study only for 20 mg of TRM-201. For Black or African-Americansubjects, the arithmetic mean AUC_(0-∞) is 3380 ng·hr/mL and thearithmetic mean C_(max) is 298 ng/mL. For Black or African-Americansubjects, the geometric mean AUC_(0-∞) is 3300 ng·hr/mL and thegeometric mean C_(max) is 295 ng/mL. For White subjects, the arithmeticmean AUC_(0-∞) is 3850 ng·hr/mL and the arithmetic mean C_(max) is 271ng/mL. For White subjects, the geometric mean AUC_(0-∞) is 3610 ng·hr/mLand the geometric mean C_(max) is 250 ng/mL.

FIG. 61 shows a summary of fasted AUC_(0-∞) and C_(max) by race for the102 PK study only for 25 mg of TRM-201. For Black or African-Americansubjects, the arithmetic mean AUC_(0-∞) is 3990 ng·hr/mL and thearithmetic mean C_(max) is 340 ng/mL. For Black or African-Americansubjects, the geometric mean AUC_(0-∞) is 3940 ng·hr/mL and thegeometric mean C_(max) is 339 ng/mL. For White subjects, the arithmeticmean AUC_(0-∞) is 4800 ng·hr/mL and the arithmetic mean C_(max) is 351ng/mL. For White subjects, the geometric mean AUC_(0-∞) is 4650 ng·hr/mLand the geometric mean C_(max) is 341 ng/mL.

FIG. 62 shows a summary of fasted AUC_(0-∞) and C_(max) by body weightfor the 102 PK study only for 12.5 mg of TRM-201. For 47-70 kg, thearithmetic mean AUC_(0-∞) is 1850 ng·hr/mL and the arithmetic meanC_(max) is 175 ng/mL. For 47-70 kg, the geometric mean AUC_(0-∞) is 1690ng·hr/mL and the geometric mean C_(max) is 165 ng/mL. For 70.1-77 kg,the arithmetic mean AUC_(0-∞) is 2500 ng·hr/mL and the arithmetic meanC_(max) is 155 ng/mL. For 70.1-77 kg, the geometric mean AUC_(0-∞) is2420 ng·hr/mL and the geometric mean C_(max) is 147 ng/mL. For 77.1-90kg, the arithmetic mean AUC_(0-∞) is 1790 ng·hr/mL and the arithmeticmean C_(max) is 127 ng/mL. For 77.1-90 kg, the geometric mean AUC_(0-∞)is 1690 ng·hr/mL and the geometric mean C_(max) is 125 ng/mL.

FIG. 63 shows a summary of fasted AUC_(0-∞) and C_(max) by body weightfor the 102 only for 17.5 mg of TRM-201. For 47-70 kg, the arithmeticmean AUC_(0-∞) is 3180 ng·hr/mL and the arithmetic mean C_(max) is 261ng/mL. For 47-70 kg, the geometric mean AUC_(0-∞) is 2930 ng·hr/mL andthe geometric mean C_(max) is 242 ng/mL. For 70.1-77 kg, the arithmeticmean AUC_(0-∞) is 3890 ng·hr/mL and the arithmetic mean C_(max) is 254ng/mL. For 70.1-77 kg, the geometric mean AUC_(0-∞) is 3730 ng·hr/mL andthe geometric mean C_(max) is 246 ng/mL. For 77.1-90 kg, the arithmeticmean AUC_(0-∞) is 2910 ng·hr/mL and the arithmetic mean C_(max) is 200ng/mL. For 77.1-90 kg, the geometric mean AUC_(0-∞) is 2850 ng·hr/mL andthe geometric mean C_(max) is 194 ng/mL.

FIG. 64 shows a summary of fasted AUC_(0-∞) and C_(max) by body weightfor the 102 PK study only for 20 mg of TRM-201. For 47-70 kg, thearithmetic mean AUC_(0-∞) is 3650 ng·hr/mL and the arithmetic meanC_(max) is 336 ng/mL. For 47-70 kg, the geometric mean AUC_(0-∞) is 3340ng·hr/mL and the geometric mean C_(max) is 307 ng/mL. For 70.1-77 kg,the arithmetic mean AUC_(0-∞) is 4500 ng·hr/mL and the arithmetic meanC_(max) is 259 ng/mL. For 70.1-77 kg, the geometric mean AUC_(0-∞) is4400 ng·hr/mL and the geometric mean C_(max) is 248 ng/mL. For 77.1-90kg, the arithmetic mean AUC_(0-∞) is 3250 ng·hr/mL and the arithmeticmean C_(max) is 238 ng/mL. For 77.1-90 kg, the geometric mean AUC_(0-∞)is 3170 ng·hr/mL and the geometric mean C_(max) is 231 ng/mL.

FIG. 65 shows a summary of fasted AUC_(0-∞) and C_(max) by body weightfor the 102 PK study only for 25 mg of TRM-201. For 47-70 kg, thearithmetic mean AUC_(0-∞) is 4450 ng·hr/mL and the arithmetic meanC_(max) is 385 ng/mL. For 47-70 kg, the geometric mean AUC_(0-∞) is 4310ng·hr/mL and the geometric mean C_(max) is 376 ng/mL. For 70.1-77 kg,the arithmetic mean AUC_(0-∞) is 5470 ng·hr/mL and the arithmetic meanC_(max) is 371 ng/mL. For 70.1-77 kg, the geometric mean AUC_(0-∞) is5410 ng·hr/mL and the geometric mean C_(max) is 368 ng/mL. For 77.1-90kg, the arithmetic mean AUC_(0-∞) is 4130 ng·hr/mL and the arithmeticmean C_(max) is 299 ng/mL. For 77.1-90 kg, the geometric mean AUC_(0-∞)is 4040 ng·hr/mL and the geometric mean C_(max) is 294 ng/mL.

FIG. 66 shows a summary of fasted AUC_(0-∞) and C_(max) by ethnicity forthe 102 PK study only for 12.5 mg of TRM-201. For Hispanic or Latinosubjects, the arithmetic mean AUC_(0-∞) is 2210 ng·hr/mL and thearithmetic mean C_(max) is 157 ng/mL. For Hispanic or Latino subjects,the geometric mean AUC_(0-∞) is 2090 ng·hr/mL and the geometric meanC_(max) is 146 ng/mL. For non-Hispanic or non-Latino subjects, thearithmetic mean AUC_(0-∞) is 1820 ng·hr/mL and the arithmetic meanC_(max) is 146 ng/mL. For non-Hispanic or non-Latino subjects, thegeometric mean AUC_(0-∞) is 1680 ng·hr/mL and the geometric mean C_(max)is 141 ng/mL.

FIG. 67 shows a summary of fasted AUC_(0-∞) and C_(max) by ethnicity forthe 102 PK study only for 17.5 mg of TRM-201. For Hispanic or Latinosubjects, the arithmetic mean AUC_(0-∞) is 3520 ng·hr/mL and thearithmetic mean C_(max) is 258 ng/mL. For Hispanic or Latino subjects,the geometric mean AUC_(0-∞) is 3330 ng·hr/mL and the geometric meanC_(max) is 243 ng/mL. For non-Hispanic or non-Latino subjects, thearithmetic mean AUC_(0-∞) is 3050 ng·hr/mL and the arithmetic meanC_(max) is 214 ng/mL. For non-Hispanic or non-Latino subjects, thegeometric mean AUC_(0-∞) is 2910 ng·hr/mL and the geometric mean C_(max)is 207 ng/mL.

FIG. 68 shows a summary of fasted AUC_(0-∞) and C_(max) by ethnicity forthe 102 PK study only for 20 mg of TRM-201. For Hispanic or Latinosubjects, the arithmetic mean AUC_(0-∞) is 3840 ng·hr/mL and thearithmetic mean C_(max) is 281 ng/mL. For Hispanic or Latino subjects,the geometric mean AUC_(0-∞) is 3630 ng·hr/mL and the geometric meanC_(max) is 258 ng/mL. For non-Hispanic or non-Latino subjects, thearithmetic mean AUC_(0-∞) is 3660 ng·hr/mL and the arithmetic meanC_(max) is 272 ng/mL. For non-Hispanic or non-Latino subjects, thegeometric mean AUC_(0-∞) is 3470 ng·hr/mL and the geometric mean C_(max)is 260 ng/mL.

FIG. 69 shows a summary of fasted AUC_(0-∞) and C_(max) by ethnicity forthe 102 PK study only for 25 mg of TRM-201. For Hispanic or Latinosubjects, the arithmetic mean AUC_(0-∞) is 4980 ng·hr/mL and thearithmetic mean C_(max) is 358 ng/mL. For Hispanic or Latino subjects,the geometric mean AUC_(0-∞) is 4870 ng·hr/mL and the geometric meanC_(max) is 351 ng/mL. For non-Hispanic or non-Latino subjects, thearithmetic mean AUC_(0-∞) is 4280 ng·hr/mL and the arithmetic meanC_(max) is 340 ng/mL. For non-Hispanic or non-Latino subjects, thegeometric mean AUC_(0-∞) is 4150 ng·hr/mL and the geometric mean C_(max)is 331 ng/mL.

FIG. 70 shows a sensitivity analysis of fasted AUC_(0-∞) and C_(max)compared to historical data. The geometric mean ratio AUC_(0-∞) ofTRM-201 17.5 mg to historical data for the 25 mg VIOXX product is 0.819.The geometric mean ratio C_(max) of TRM-201 17.5 mg to historical datafor the 25 mg VIOXX product is 1.03. The geometric mean ratio AUC_(0-∞)of TRM-201 20 mg to historical data for the 25 mg VIOXX product is0.934. The geometric mean ratio C_(max) of TRM-201 20 mg to historicaldata for the 25 mg VIOXX product is 1.19. The AUC_(0-∞) and C_(max) datafor the 25 mg VIOXX product were obtained from Schwartz, J. I., et al.Clin. Drug Invent. 2003, 23(8): 503-509.

FIG. 71 shows a summary of fasted T_(max) and t_(1/2) for the 101 and102 PK studies combined. The median time at which the C_(max) isobserved (T_(max)) for 12.5 mg of TRM-201 is 2.00 hours. The medianT_(max) for 17.5 mg of TRM-201 is 2.00 hours. The T_(max) for 20 mg ofTRM-201 is 2.00 hours. The T_(max) for 25 mg of TRM-201 is 2.50 hours.The median t_(1/2) for 12.5 mg of TRM-201 is 12 hours. The t_(1/2) isgenerally comparable across dosages. The median t_(1/2) for 17.5 mg ofTRM-201 is 11.7 hours. The median t_(1/2) for 20 mg of TRM-201 is 12.2hours. The median t_(1/2) for 25 mg of TRM-201 is 11.6 hours.

FIG. 72 shows a summary of fasted CL/F and V_(d)/F for the 102 PK studyonly. FIG. 73 shows exploratory analysis of fasted AUC_(0-∞) and C_(max)to estimate the dose that yields values equal to those observed in thehistorical data (for the 102 PK study only). FIG. 74 shows summary oftreatment-emergent adverse events (TEAE). A total of three subjectsexhibited a TEAE in the 102 PK study. One of these subjects wasadministered 12.5 mg of TRM-201 and the other two subjects wereadministered 25 mg of TRM-201. No subjects exhibited related TEAE,serious TEAE, TEAE leading to study discontinuation, or severe TEAE.

FIG. 75 shows incidence of treatment-emergent adverse events (TEAE) bysystem organ class and preferred term. At 12.5 mg of TRM-201, the TEAEin preferred term was constipation. At 25 mg of TRM-201, the TEAE inpreferred term was ear discomfort and headache.

FIG. 76 shows no incidence of related TEAE at any dosage. FIG. 77 showsno incidence of serious TEAE at any dosage. FIG. 78 shows no incidenceof TEAE leading to study discontinuation at any dosage. FIG. 79 showsincidence of TEAE by system organ class, preferred term, and severity.All reported TEAE were mild.

FIG. 80 shows arithmetic mean (SD) fasted rofecoxib concentration acrossscheduled time profiles on the linear scale. The peak rofecoxibconcentration was observed between 0 and 5 hours followingadministration for all dosages. FIGS. 81-84 show arithmetic mean (SD)fasted rofecoxib concentration across scheduled time profiles on thelinear scale presented by dosage.

FIG. 85 shows arithmetic mean fasted concentration across scheduled timeprofiles on the linear scale across dosages without standard deviations.

FIG. 86 shows geometric mean (SD) fasted concentration across scheduledtime profile on the semi-logarithmic scale. The peak rofecoxibconcentration was observed between 0 and 5 hours followingadministration for all dosages. FIGS. 87-90 show geometric mean (SD)fasted concentration of rofecoxib across scheduled time profiles on thesemi-logarithmic scale broken down by concentration.

FIG. 91 shows geometric mean fasted concentration versus scheduled timeprofiles on the semi-logarithmic scale for all dosages without standarddeviations.

FIG. 92 shows a scatterplot of fasted AUC_(0-∞) values by age and byTRM-201 dosage. FIG. 93 shows a scatterplot of fasted AUC_(0-∞) valuesby race and by TRM-201 dosage. FIG. 94 shows a scatterplot of fastedAUC_(0-∞) values by body weight and by TRM-201 dosage. FIG. 95 shows ascatterplot of fasted AUC_(0-∞) values by BMI and by TRM-201 dosage.

FIG. 96 shows a scatterplot of fasted C_(max) values by age and byTRM-201 dosage. FIG. 97 shows a scatterplot of fasted C_(max) values byrace and by TRM-201 dosage. FIG. 98 shows a scatterplot of fastedC_(max) values by body weight and by TRM-201 dosage. FIG. 99 shows ascatterplot of fasted C_(max) values by BMI and by TRM-201 dosage.

FIG. 100 shows a scatterplot of fasted AUC_(0-∞) and C_(max) values,dose-adjusted on raw scale, for each TRM-201 dosage. FIG. 101 shows ascatterplot of fasted AUC_(0-∞) and C_(max) values, not dose-adjusted onnatural-log scale, for each TRM-201 dosage. FIGS. 102A-B show a boxplotof fasted AUC_(0-∞) and C_(max) indices, respectively, for each dosage.

FIGS. 103-104 show a comparison of the mean plasma concentration (ng/L)versus time for TRM-201 20 mg and the 25 mg “VIOXX” tablet and oralsuspension products reported in Schwartz, J. I., et al. Clin. DrugInvent. 2003, 23 (8): 503-509.

Unexpected Results

The FDA-approved label for the “VIOXX” product provided that “[t]hepharmaco-kinetics of rofecoxib are comparable in men and women,” andthat “[m]eta-analysis of pharmacokinetic studies has suggested aslightly (10-15%) higher AUC of rofecoxib in Blacks and Hispanics ascompared to Caucasians.” See the “VIOXX” label at p. 2.

In some embodiments, the subject matter disclosed herein relates to thesurprising and unexpected discovery that certain of the formulations andmethods described herein can achieve different pharmacokinetic profilesin men and women following single administration of the same amount ofrofecoxib, contrary to what was described in the FDA-approved label forthe “VIOXX” product. It was also surprisingly and unexpectedlydiscovered that certain of the formulations and methods described hereincan achieve a higher AUC in Caucasian subjects than African Americansubjects following single administration of the formulations comprisingrofecoxib as described herein.

References for Example 6

-   Bresalier R S, Sandler R S, Quan H, et al. Cardiovascular events    associated with rofecoxib in a colorectal adenoma chemoprevention    trial. New Engl J Med 2005; 352:1092-102.-   Matthews C Z, Woolf E J, Matuszewski B K. Improved procedure for the    determination of rofecoxib in human plasma involving 96-well    solid-phase extraction and fluorescence detection. J Chromatogr A.    2002; 949(1-2):83-9.-   Schwartz J I, Larson P J, Porras A G, et al. Pharmacokinetic    evaluation of rofecoxib: comparison of tablet and suspension    formulations. Clin Drug Invest. 2003; 23(8):503-9.-   Tsoukas C, Eyster M E, Shingo S, et al. Evaluation of the efficacy    and safety of etoricoxib in the treatment of hemophilic arthropathy.    Blood. 2006; 107(5):1785-90.-   U.S. Food and Drug Administration. Analysis and recommendations for    agency action regarding nonsteroidal antiinflammatory drugs and    cardiovascular risk. J Pain Palliat Care Pharmacother. 2005;    19(4):83-97.-   Vioxx (rofecoxib) [package insert]. Merck & Co., Inc. Whitehouse    Station, N.J.; 2016.

Example 7—Bioanalytical Method to Measure Rofecoxib PlasmaConcentrations Introduction

In order to support clinical studies with TRM-201 (rofecoxib), a methodwas developed for the determination of rofecoxib in human plasma byLC-MS/MS. This method was validated in accordance with the FDA GoodLaboratory Practice Regulations (GLP) as set forth in Title 21 of theU.S. Code of Federal Regulations Part 58 as well as FDA Guidance forIndustry: Bioanalytical Method Validation, May 2018. A summary of thevalidated method is provided in Table 22.

TABLE 22 Validation Summary for Rofecoxib Report Title Validation of aMethod for the Determination of Rofecoxib in Human Plasma by LC-MS/MSAnalyte Name Rofecoxib Internal Standard (IS) Rolccoxib-d₅ AnalyticalMethod Type LC-MS/MS Extraction Method Liquid-liquid Sample Volume 100μL QC Concentrations 0.5, 1.5, 20, 200, and 400 ng/mL Standard CurveConcentrations 0.5, 1, 5, 10, 50, 100, 450, and 500 ng/mL Lower Limit OfQuantitation 0.5 ng/mL Upper Limit Of Quantitation 500 ng/mL MeanRecovery of Analyte (%) 92.6 Mean Recovery of Internal 92.7 Standard (%)Variation of Matrix Effect from ≤2.6 Six Lots ofMatrix (% CV)Sensitivity Analyte response [LLOQ/zero calibrator (i.e.Blank + IS)] >five LLOQ QC Intra-run Precision 2.0 to 7.8 Range (% CV) LLOQ QCIntra-run Accuracy −11.8 to −1.8 Range (% RE) Analytical QC Intra-runPrecision 0.8 to 6.6 Range (% CV) Analytical QC Intra-run Accuracy −4.0to 3.0 Range (% RE) LLOQ QC Inter-run Precision 7.3 (% CV) LLOQ QCInter-run Accuracy −5.2 (% RE) Analytical QC Inter-run Precision 3.0 to4.9 Range (% CV) Analytical QC Inter-run Accuracy −2.5 to 0.7 Range (%RE) Stock Solution Stability in 202 Days at −20° C. Dimethyl Sulfoxide17 Hours at Ambient Temperature Processed Sample Stability 174 Hours at4° C. Benchtop Stability in Plasma 26 Hours at Ambient TemperatureFreeze/Thaw Stability in Plasma 5 Cycles at −20° C. and −70° C. BenchtopStability in Whole 2 Hours in an Ice Bath when Blood Centrifuged at 4°C. or Ambient Temperature Long-term Storage Stability in 184 Days at−20° C. and −70° C. Plasma Dilution Integrity 1000 ng/mL diluted 20-foldSelectivity ≤20.0% LLOQ for analyte; ≤5.0% for IS Spike-in SelectivityMeets Acceptance Criteria 2% Hemolyzed Plasma Test No impact on assayperformance Lipemic Plasma Test No impact on assay performance BatchSize Test 192 Injections Carryover <20% LLOQ (Rofecoxib) <5% CarryoverIS (Rofecoxib-d₅)

EQUIVALENTS

The invention can be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting on the invention described herein.

1-30. (canceled)
 31. A solid dosage formulation comprising 17.5 mg ofrofecoxib, or a pharmaceutically acceptable salt thereof, wherein theformulation achieves a mean C_(max) plasma concentration of more than180 ng/ml following oral administration of a single dose of theformulation to a population of healthy adults less than 65 years of age.32. The solid dosage formulation of claim 31, wherein the formulationachieves a mean C_(max) plasma concentration of more than 190 ng/mlfollowing oral administration of a single dose of the formulation to apopulation of healthy adults less than 65 years of age.
 33. The soliddosage formulation of claim 32, wherein the formulation achieves a meanC_(max) plasma concentration of more than 200 ng/ml following oraladministration of a single dose of the formulation to a population ofhealthy adults less than 65 years of age.
 34. The solid dosageformulation of claim 33, wherein the formulation achieves a mean C_(max)plasma concentration of about 224 ng/ml following oral administration ofa single dose of the formulation to a population of healthy adults lessthan 65 years of age.
 35. The solid dosage formulation of claim 31,wherein the formulation achieves a mean C_(max) plasma concentrationwithin 80-125% of 224 ng/ml following oral administration of a singledose of the formulation to a population of healthy adults less than 65years of age.
 36. The solid dosage formulation of claim 31, wherein theformulation achieves a mean plasma AUC_(0-∞) of more than 3000 h*ng/mlfollowing oral administration of a single dose of the formulation to apopulation of healthy adults less than 65 years of age.
 37. The soliddosage formulation of claim 31, wherein the formulation achieves ahigher mean plasma C_(max) and a higher mean plasma AUC_(0-∞) in apopulation of healthy female adults less than 65 years of age comparedto a population of healthy male adults less than 65 years of agefollowing oral administration of a single dose of the formulation. 38.The solid dosage formulation of claim 31, wherein the formulationachieves a higher mean plasma AUC_(0-∞) in Caucasian adults less than 65years of age compared to healthy African American adults less than 65years of age following oral administration of a single dose of theformulation.
 39. The solid dosage formulation of claim 31, wherein theformulation achieves an arithmetic mean plasma concentration of at least2.0 ng/ml at 15 minutes following oral administration of a single doseof the formulation to a population of healthy adults less than 65 yearsof age.
 40. The solid dosage formulation of claim 31, wherein theformulation achieves an arithmetic mean plasma concentration of at least79 ng/ml at 45 minutes following oral administration of a single dose ofthe formulation to a population of healthy adults less than 65 years ofage.
 41. The solid dosage formulation of claim 31, wherein the soliddosage formulation further comprises a disintegrant.
 42. The soliddosage formulation of claim 31, wherein the rofecoxib has a d90 particlesize in the range of about 10 μm to about 12 μm, a d50 particle size inthe range of about 3 μm to about 4 μm, and a d10 particle size in therange of about 0.5 μm to about 1.0 μm.
 43. A solid dosage formulationcomprising 17.5 mg of rofecoxib, or a pharmaceutically acceptable saltthereof, wherein the formulation achieves a mean plasma AUC_(0-∞) ofmore than 3000 h*ng/ml following oral administration of a single dose ofthe formulation to a population of healthy adults less than 65 years ofage.
 44. The solid dosage formulation of claim 43, wherein theformulation achieves a mean C_(max) plasma concentration of more than167 ng/ml following oral administration of a single dose of theformulation to a population of healthy adults less than 65 years of age.45. The solid dosage formulation of claim 44, wherein the formulationachieves a mean C_(max) plasma concentration of about 224 ng/mlfollowing oral administration of a single dose of the formulation to apopulation of healthy adults less than 65 years of age.
 46. The soliddosage formulation of claim 43, wherein the formulation achieves a meanC_(max) plasma concentration within 80-125% of 224 ng/ml following oraladministration of a single dose of the formulation to a population ofhealthy adults less than 65 years of age.
 47. The solid dosageformulation of claim 43, wherein the formulation achieves a higher meanplasma C_(max) and a higher mean plasma AUC_(0-∞) in a population ofhealthy female adults less than 65 years of age compared to a populationof healthy male adults less than 65 years of age following oraladministration of a single dose of the formulation.
 48. The solid dosageformulation of claim 43, wherein the formulation achieves a higher meanplasma AUC_(0-∞) in Caucasian adults less than 65 years of age comparedto healthy African American adults less than 65 years of age followingoral administration of a single dose of the formulation.
 49. The soliddosage formulation of claim 43, wherein the formulation achieves anarithmetic mean plasma concentration of at least 2.0 ng/ml at 15 minutesfollowing oral administration of a single dose of the formulation to apopulation of healthy adults less than 65 years of age.
 50. The soliddosage formulation of claim 43, wherein the formulation achieves anarithmetic mean plasma concentration of at least 79 ng/ml at 45 minutesfollowing oral administration of a single dose of the formulation to apopulation of healthy adults less than 65 years of age.
 51. The soliddosage formulation of claim 43, wherein the solid dosage formulationfurther comprises a disintegrant.
 52. The solid dosage formulation ofclaim 43, wherein the rofecoxib has a d90 particle size in the range ofabout 10 μm to about 12 μm, a d50 particle size in the range of about 3μm to about 4 μm, and a d10 particle size in the range of about 0.5 μmto about 1.0 μm.
 53. A solid dosage formulation comprising 17.5 mg ofrofecoxib, or a pharmaceutically acceptable salt thereof, wherein theformulation achieves an arithmetic mean plasma concentration of at least2.0 ng/ml at 15 minutes following oral administration of a single doseof the formulation to a population of healthy adults less than 65 yearsof age.
 54. The solid dosage formulation of claim 53, wherein theformulation achieves an arithmetic mean plasma concentration of at least79 ng/ml at 45 minutes following oral administration of a single dose ofthe formulation to a population of healthy adults less than 65 years ofage.
 55. The solid dosage formulation of claim 53, wherein theformulation achieves a mean C_(max) plasma concentration of more than167 ng/ml following oral administration of a single dose of theformulation to a population of healthy adults less than 65 years of age.56. The solid dosage formulation of claim 53, wherein the formulationachieves a mean C_(max) plasma concentration within 80-125% of 224 ng/mlfollowing oral administration of a single dose of the formulation to apopulation of healthy adults less than 65 years of age.
 57. The soliddosage formulation of claim 53, wherein the formulation achieves ahigher mean plasma C_(max) and a higher mean plasma AUC_(0-∞) in apopulation of healthy female adults less than 65 years of age comparedto a population of healthy male adults less than 65 years of agefollowing oral administration of a single dose of the formulation. 58.The solid dosage formulation of claim 53, wherein the formulationachieves a higher mean plasma AUC_(0-∞) in Caucasian adults less than 65years of age compared to healthy African American adults less than 65years of age following oral administration of a single dose of theformulation.
 59. The solid dosage formulation of claim 53, wherein thesolid dosage formulation further comprises a disintegrant.
 60. The soliddosage formulation of claim 53, wherein the rofecoxib has a d90 particlesize in the range of about 10 μm to about 12 μm, a d50 particle size inthe range of about 3 μm to about 4 μm, and a d10 particle size in therange of about 0.5 μm to about 1.0 μm.